Benzimidazole derivatives as ERBB tyrosine kinase inhibitors for the treatment of cancer

ABSTRACT

Provided herein are benzimidazole derivatives, for example, of Formula (I), and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a proliferative disease.

CROSS REFERENCE TO RELATED APPLICATION

This application is a Divisional Application of U.S. application Ser.No. 15/127,000, filed Sep. 16, 2016; which is a National Stage ofInternational Application No. PCT/US2015/021475, filed Mar. 19, 2015;which claims the benefit of the priority of U.S. Provisional ApplicationNo. 61/968,243, filed Mar. 20, 2014; the disclosure of each of which isincorporated by reference in its entirety.

FIELD

Provided herein are benzimidazole derivatives and pharmaceuticalcompositions thereof. Also provided herein are methods of their use fortreating, preventing, or ameliorating one or more symptoms of aproliferative disease.

BACKGROUND

In the human receptor tyrosine kinase superfamily, the ERBB familycomprises four members: ERBB1 (epidermal growth factor receptor orEGFR), ERBB2 (HER2), ERBB3 (HER3), and ERBB4 (HER4). The ERBB receptorsshare an overall similar structure with a ligand-binding ectodomain, asingle transmembrane domain, and an intracellular kinase domain, whichis active in ERBB1, HER2 and ERBB4, but defective in ERBB3. A diversearray of ligands has been identified for the ectodomains of ERBB1,ERBB3, and ERBB4, but not HER2. Ligand binding induces conformationalchange in receptors to form homo- and hetero-dimerization. Withoutligand binding, the extracellular domain of HER2 is already fixed in aconformation that resembles the other ligand-activated ERBB members,making it a preferred dimerization partner for other ligand-bound ERBBs.The dimerized receptors activate the intrinsic kinase activity, leadingto phosphorylation of tyrosines at cytoplasmic tails. The ERBB receptorsdiffer in kinase potency, phosphorylation sites, and substratespecificity. The phosphorylated tyrosines serve as the docking sites torecruit downstream effectors and activate multiple cascades ofintracellular signaling pathways, including the anti-apoptotic/survivalPI3K/AKT and the mitogenic RAS/RAF/MEK/ERK pathways. In normal cells,the activity of ERBB receptors is under tight control to regulatevarious cellular processes, such as growth, proliferation, developmentand differentiation, survival and apoptosis, cell shape and adhesion,migration, and angiogenesis. Yarden et al., Nat. Rev. Mol. Cell. Biol.2001, 2, 127-137; Hynes et al., Nat. Rev. Cancer 2005, 5, 341-354.

As a major proliferation and survival engine for cells, constitutiveactivation of ERBB receptors, particularly ERBB1 and HER2, is oncogenicand can be a strong driver for tumorigenesis in cultured cells andanimal models. In addition, the activated receptors accelerate cancerdevelopment by promoting tumor angiogenesis and metastasis. Persistentactivation can result from overexpression of the receptors, productionof excessive ligands, or generation of activating mutations in theectodomains and kinase domains of the receptors. Yarden et al., Nat.Rev. Mol. Cell. Biol. 2001, 2, 127-137. In humans, genetic alterationsin ERBB genes and other genes that lead to similar deregulation of ERBBreceptors are frequently identified in majority of carcinomas, such aslung, breast, colon, prostate, brain, head and neck, oesophagus, ovary,cervix, bladder, stomach, and endometrium cancer. The aberrantactivation of ERBB receptors is in general an adverse prognosticindicator for higher recurrence rate and shorter survival time.Nicholson et al., Eur. J. Cancer 2001, 37, 9-15; Slamon et al., Science1997, 235, 177-182.

Given the compelling association of activation of ERBB receptors withhuman cancers, ERBB1 and HER2 are among the kinase targets for drugdevelopment, aiming to tame signaling transduction pathways for cancertreatment. To reverse the abnormal activity of ERBB receptors in tumors,monoclonal antibodies targeting the extracellular domains of ERBB1 andHER2 and small molecule chemicals inhibiting the intracellular kinasedomains have been developed.

The monoclonal antibody drugs attack the ERBB receptors with highspecificity and attenuate ERBB-mediated signaling by prevention ofligand binding and receptor dimerization, elimination receptors fromcell surface through endocytosis, inhibition of shedding ofextracellular domain, and activation of immune system. Hudis, N. Engl.J. Med. 2007, 357, 39-51. Cetuximab and panitumumab, two anti-ERBB1antibodies, have shown improvement in response rate and the rate ofprogression-free survival in the treatment of metastatic colon cancereither as monotherapy or in combination with chemotherapies. Inaddition, cetuximab has also been approved for the treatment of locallyadvanced, unresectable or metastatic squamous cell carcinoma of the headand neck. Ciardiello et al., N. Engl. J. Med. 2008, 358, 1160-1174.Anti-HER2 antibody trastuzumab binds to the domain IV of the HER2receptor at the juxtamembrane position. In clinical development,trastuzumab has demonstrated increased overall survival rate in early-and metastatic-stage breast cancer patients with tumors showing IHC 3+HER2 overexpression or FISH gene amplification ratio of at least 2.0.Using the same criteria for patient selection, pertuzumab, which bindsto a distinct epitope at the domain II of the HER2 receptor, has beenfound to further increase the complete response rate by addition totrastuzumab and docetaxel regimen as a neoadjuvant treatment forpatients with locally advanced, early-stage breast cancer. Gradishar, N.Engl. J. Med. 2012, 366, 176-178.

Development of small-molecule ERBB1 kinase inhibitors (ERBB1Is) hasbecome an evolving paradigm for using cancer genomics to guide targeteddrug development and treatment. Gefinitib and erlotinib, the first twoERBB1I drugs, are reversible ATP mimetic inhibitors that bind to thewild-type ERBB1 catalytic domain to inhibit tyrosine kinase activity. Inunselected patients of non-small cell lung cancer (NSCLC) or pancreaticcancer, only erlotinib has demonstrated clinical benefit by modestlyincreasing overall survival. Ciardiello et al., N. Engl. J. Med. 2008,358, 1160-1174. In a subset of NSCLC patients that harbor activatingmutations within ERBB1 tyrosine kinase domain, both gefitinib anderlotinib treatments are highly sensitive and can achieve lastingefficacy as monotherapy. These drug-responding mutations are mostlyin-frame deletions nested around Leu-Arg-Glu-Ala from position 747 to750 in ERBB1 exon 19, or a leucine to arginine substitution at position858 (L858R) in exon 21.

However, the initial response to erlotinib or gefitinib relapses in10-14 months by developing resistant mutations in tumors. Among them, aT790M gate-keeper point mutation in the exon 20 of ERBB1, which poses asteric interference to drug binding, is found in over 50% of acquiredresistant tumors. To overcome the resistance from T790M mutation andconfer sustained ERBB1 inhibition, the second-generation ERBB1Is havebeen developed, some of them are irreversible ERBB1 and HER2 dualinhibitors. The irreversible compounds overcome the kinase bindinghindrance from T790M mutation by better fitting into the mutated bindingpocket and forming covalent bond with the protein amino acid residues.Additionally, irreversible ERBB1Is appear to cause slower acquiredresistance to the treatment than reversible inhibitors. Sharma et al.,Nat. Rev. Cancer 2007, 7, 169-181.

In preclinical testing, afatinib, a second-generation ERBB1I, inhibitedthe growth of NSCLC HCC827 cells, which harbor the sensitive exon 19deletion, and is 50-fold more potent than erlotinib in inhibition ofgrowth of NSCLC H1975 cells, which has a T790M mutation in-cis with theL858R mutation. However, afatinib also inhibits A431 cells, whose growthis driven by a wild-type ERBB1, 100-fold more potent than H1975. Thedifference in potencies portends that, in cancer patients, the compoundcould inhibit wild-type ERBB1 completely before it reaches sufficientblood level for pharmacological effect on T790M mutant ERBB1. Sincewild-type ERBB1 inhibition has been reported to cause dose-limitingtoxicity in virtually all previously ERBB1I drugs, the preferentialinhibition of wild-type ERBB1 over resistant mutant pose a potentialchallenge for afatinib to achieve high enough dose for T790M mutantinhibition. Consistent with the preclinical discovery, clinicaldevelopment has found afatinib only showed equivalent efficacy toerlotinib or gefitinib in patients with sensitive mutations, but failedto demonstrate statistically meaningful superiority to erlotinib andgefitinib in treating patients with acquired T790M resistant mutationeven at the maximum tolerated dose. Langer, J. Clin. Oncol. 2013, 31,3303-3330. Thus, there is a clear and unmet need to develop effectivetherapeutics for treating a proliferative disease, especiallydrug-resistant cancer.

SUMMARY OF THE DISCLOSURE

Provided herein is a compound of Formula I:

or a single enantiomer, a racemic mixture, a mixture of diastereomers,or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof;

R¹ is (a) hydrogen, cyano, halo, or nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl,or heterocyclyl; (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); or (d)—C(O)CR^(1e)═CR^(1f)CR^(1g),

—N^(1a)C(O)CR^(1e)═CR^(1f)CR^(1g),

—S(O)CR^(1e)═CR^(1f)CR^(1g),

—S(O₂)CR^(1e)═CR^(1f)CR^(1g),

—NR^(1a)S(O)CR^(1e)═CR^(1f)CR^(1g),

—NR^(1a)S(O₂)CR^(1e)═CR^(1f)CR^(1g), or

R² is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl;

L¹ is a bond, —O—, —S—, —N(R^(1A))—, or —C(R^(1A)R^(1B))—, wherein eachR^(1A) and R^(1B) is independently hydrogen, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl;

L² is C₃₋₁₀ cycloalkylene, C₆₋₁₄ arylene, C₇₋₁₅ aralkylene,heteroarylene, or heterocyclylene;

T is a bond, —O—, —S—, —N═, —N(R⁴)—, or —C(R⁴)═;

U is a bond, —O—, —S—, —N═, —N(R⁵)—, or —C(R⁵)═;

V is a bond, —O—, —S—, —N═, —N(R⁶)—, or —C(R⁶)═;

W is a bond, —O—, —S—, —N═, —N(R⁷)—, or —C(R⁷)═;

X and Y are each independently C or N;

Z is NR^(2A) or CR^(2A)R^(2B), wherein each R^(2A) and R^(2B) isindependently hydrogen, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl;

R⁴, R⁵, R⁶, and R⁷ are each independently (a) hydrogen, cyano, halo, ornitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c)—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); with proviso that at leasttwo of R⁴, R⁵, R⁶, and R⁷ are not hydrogen; and with the proviso that R⁴and R⁵, R⁵ and R⁶, or R⁶ and R⁷ are linked together to form heteroarylor heterocyclyl;

each R^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or R^(1a) and R^(1c) together withthe C and N atoms to which they are attached form heterocyclyl; orR^(1b) and R^(1c) together with the N atom to which they are attachedform heterocyclyl; and

each R^(1e), R^(1f), and R^(1g) is independently hydrogen, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl;

with the proviso that no more than one of T, U, V, and W is a bond;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl,arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl,and heterocyclylene is optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q, where each Q isindependently selected from (a) oxo, cyano, halo, and nitro; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, and heterocyclyl, each of which is furtheroptionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q^(a); and (c) —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c),—OP(O)(OR^(a))₂, —OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c),—OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)₂NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and—S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b), R^(c), and R^(d) isindependently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl,each of which is optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q^(a); or (iii) R^(b)and R^(c) together with the N atom to which they are attached formheterocyclyl, optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q^(a);

wherein each Q^(a) is independently selected from the group consistingof (a) oxo, cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl; and (c) —C(O)R^(f), —C(O)OR^(f), —C(O)NR^(g)R^(h),—C(NR^(f))NR^(g)R^(h), —OR^(f), —OC(O)R^(f), —OC(O)OR^(f),—OC(O)NR^(g)R^(h), —OC(═NONR^(g)R^(h), —OP(O)(OR^(f))₂, —OS(O)R^(f),—OS(O)₂R^(f), —OS(O)NR^(g)R^(h), —OS(O)₂NR^(g)R^(h), —NR^(g)R^(h),—NR^(f)C(O)R^(k), —NR^(f)C(O)OR^(k), —NR^(f)C(O)NR^(g)R^(h),—NR^(f)C(═NR^(k))NR^(g)R^(h), —NR^(f)S(O)R^(k), —NR^(f)S(O)₂R^(k),—NR^(f)S(O)NR^(g)R^(h), —NR^(f)S(O)₂NR^(g)R^(h), —SR^(f), —S(O)R^(f),—S(O)₂R^(f), —S(O)NR^(g)R^(h), and —S(O)₂NR^(g)R^(h); wherein eachR^(f), R^(g), R^(h), and R^(k) is independently (i) hydrogen; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(g) and R^(h) togetherwith the N atom to which they are attached form heterocyclyl.

Also provided herein are pharmaceutical compositions comprising acompound disclosed herein, e.g., a compound of Formula I, or a singleenantiomer, a racemic mixture, a mixture of diastereomers, or anisotopic variant thereof or a pharmaceutically acceptable salt, solvate,or prodrug thereof and optionally a pharmaceutically acceptableexcipient or carrier.

Furthermore, provided herein is a method for treating, preventing, orameliorating one or more symptoms of a proliferative disease in asubject, comprising administering to the subject a compound disclosedherein, e.g., a compound of Formula I, or a single enantiomer, a racemicmixture, a mixture of diastereomers, or an isotopic variant thereof or apharmaceutically acceptable salt, solvate, or prodrug thereof.

Provided herein is a method for treating, preventing, or amelioratingone or more symptoms of an ERBB-mediated condition, disorder, or diseasein a subject, comprising administering to the subject a compounddisclosed herein, e.g., a compound of Formula I, or a single enantiomer,a racemic mixture, a mixture of diastereomers, or an isotopic variantthereof or a pharmaceutically acceptable salt, solvate, or prodrugthereof.

Provided herein is a method for treating, preventing, or amelioratingone or more symptoms of cancer in a subject, comprising administering tothe subject a compound disclosed herein, e.g., a compound of Formula I,or a single enantiomer, a racemic mixture, a mixture of diastereomers,or an isotopic variant thereof or a pharmaceutically acceptable salt,solvate, or prodrug thereof. In one embodiment, the cancer isdrug-resistant.

Provided herein is a method of inhibiting the growth of a cell,comprising contacting the cell with a compound provided herein, e.g., acompound of Formula I, or a single enantiomer, a racemic mixture, amixture of diastereomers, or an isotopic variant thereof or apharmaceutically acceptable salt, solvate, or prodrug thereof.

Provided herein is a method of inhibiting the growth of a cell in asubject, comprising administering to the subject a compound disclosedherein, e.g., a compound of Formula I, or a single enantiomer, a racemicmixture, a mixture of diastereomers, or an isotopic variant thereof; ora pharmaceutically acceptable salt, solvate, or prodrug thereof.

Provided herein is a method for modulating the activity of a tyrosinekinase, in one embodiment, an ERBB kinase, comprising contacting theERBB kinase with a compound disclosed herein, e.g., a compound ofFormula I, or a single enantiomer, a racemic mixture, a mixture ofdiastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof.

Provided herein is a method for modulating the activity of a tyrosinekinase, in one embodiment, an ERBB kinase, in a subject, comprisingadministering to the subject a compound disclosed herein, e.g., acompound of Formula I, or a single enantiomer, a racemic mixture, amixture of diastereomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, or prodrug thereof.

DETAILED DESCRIPTION

To facilitate understanding of the disclosure set forth herein, a numberof terms are defined below.

Generally, the nomenclature used herein and the laboratory procedures inbiology, biochemistry, medicinal chemistry, organic chemistry, andpharmacology described herein are those well known and commonly employedin the art. Unless defined otherwise, all technical and scientific termsused herein generally have the same meaning as commonly understood byone of ordinary skill in the art to which this disclosure belongs.

The term “tumor,” “neoplasm,” and “neoplastic disorder or disease” areused interchangeably herein and are meant to refer to unwanted cellproliferation of one or more subset of cells in a multicellular organismresulting in harm (i.e., discomfort or decreased life expectancy) to themulticellular organisms. In certain embodiments, a tumor can be benign(non-invasive) or malignant (invasive).

The term “cancer” is meant to refer to a malignant neoplasm, which ischaracterized by uncontrolled cell proliferation where cells have losttheir normal regulatory controls that would otherwise govern the rate ofcell growth. These unregulated, dividing cells can spread throughout thebody and invade normal tissues in a process referred to as “metastasis.”

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit,rat, and mouse. The terms “subject” and “patient” are usedinterchangeably herein in reference, for example, to a mammaliansubject, such as a human subject, in one embodiment, a human.

The terms “treat,” “treating,” and “treatment” are meant to includealleviating or abrogating a condition, disorder, or disease, or one ormore of the symptoms associated with the condition, disorder, ordisease; or alleviating or eradicating the cause(s) of the condition,disorder, or disease itself.

The terms “prevent,” “preventing,” and “prevention” are meant to includea method of delaying and/or precluding the onset of a condition,disorder, or disease, and/or its attendant symptoms; barring a subjectfrom acquiring a condition, disorder, or disease; or reducing asubject's risk of acquiring a condition, disorder, or disease.

The term “contacting” or “contact” is meant to refer to bringingtogether of a therapeutic agent and cell or tissue such that aphysiological and/or chemical effect takes place as a result of suchcontact. Contacting can take place in vitro, ex vivo, or in vivo. In oneembodiment, a therapeutic agent is contacted with a cell in cell culture(in vitro) to determine the effect of the therapeutic agent on the cell.In another embodiment, the contacting of a therapeutic agent with a cellor tissue includes the administration of a therapeutic agent to asubject having the cell or tissue to be contacted.

The term “therapeutically effective amount” are meant to include theamount of a compound that, when administered, is sufficient to preventdevelopment of, or alleviate to some extent, one or more of the symptomsof the condition, disorder, or disease being treated. The term“therapeutically effective amount” also refers to the amount of acompound that is sufficient to elicit the biological or medical responseof a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell,tissue, system, animal, or human, which is being sought by a researcher,veterinarian, medical doctor, or clinician.

The term “IC₅₀” or “EC₅₀” refers an amount, concentration, or dosage ofa compound that is required for 50% inhibition of a maximal response inan assay that measures such a response.

The term “GC₅₀” refers an amount, concentration, or dosage of a compoundthat is required to reduce the viability of cells treated with thecompound by 50%, in comparison with cells untreated with the compound.

The term “CC₅₀” refers an amount, concentration, or dosage of a compoundthat results in 50% reduction of the viability of a host. In certainembodiments, the CC₅₀ of a compound is the amount, concentration, ordosage of the compound that is required to reduce the viability of cellstreated with the compound by 50%, in comparison with cells untreatedwith the compound.

The term “relapsed” refers to a situation where a subject, who has had aremission of cancer after therapy has a return of cancer cells.

The term “refractory or resistant” refers to a circumstance where asubject, even after intensive treatment, has residual cancer cells inhis body.

The term “drug resistance” refers to the condition when a disease doesnot respond to the treatment of a drug or drugs. Drug resistance can beeither intrinsic, which means the disease has never been responsive tothe drug or drugs, or it can be acquired, which means the disease ceasesresponding to a drug or drugs that the disease had previously respondedto. In certain embodiments, drug resistance is intrinsic. In certainembodiments, the drug resistance is acquired.

The term “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” or“physiologically acceptable excipient” refers to apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, solvent, or encapsulating material. Inone embodiment, each component is “pharmaceutically acceptable” in thesense of being compatible with the other ingredients of a pharmaceuticalformulation, and suitable for use in contact with the tissue or organ ofhumans and animals without excessive toxicity, irritation, allergicresponse, immunogenicity, or other problems or complications,commensurate with a reasonable benefit/risk ratio. See, Remington: TheScience and Practice of Pharmacy, 21st ed.; Lippincott Williams &Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the AmericanPharmaceutical Association: 2012; Handbook of Pharmaceutical Additives,3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007;Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRCPress LLC: Boca Raton, Fla., 2009.

The term “about” or “approximately” means an acceptable error for aparticular value as determined by one of ordinary skill in the art,which depends in part on how the value is measured or determined. Incertain embodiments, the term “about” or “approximately” means within 1,2, 3, or 4 standard deviations. In certain embodiments, the term “about”or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%,4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

The terms “active ingredient” and “active substance” refer to acompound, which is administered, alone or in combination with one ormore pharmaceutically acceptable excipients, to a subject for treating,preventing, or ameliorating one or more symptoms of a condition,disorder, or disease. As used herein, “active ingredient” and “activesubstance” may be an optically active isomer or an isotopic variant of acompound described herein.

The terms “drug,” “therapeutic agent,” and “chemotherapeutic agent”refer to a compound, or a pharmaceutical composition thereof, which isadministered to a subject for treating, preventing, or ameliorating oneor more symptoms of a condition, disorder, or disease.

The term “naturally occurring” or “native” when used in connection withbiological materials such as nucleic acid molecules, polypeptides, hostcells, and the like, refers to materials which are found in nature andare not manipulated by man. Similarly, “non-naturally occurring” or“non-native” refers to a material that is not found in nature or thathas been structurally modified or synthesized by man.

The term “ERBB” or “ERBB kinase” refers to a tyrosine kinase of the ERBBfamily or a variant thereof, including, but not limited to, ERBB1 (EGFRor HER1), ERBB2 (HER2/c-neu), ERBB3 (HER3), and ERBB4 (HER4). ERBBvariants include proteins substantially homologous to a native ERBBkinase, i.e., proteins having one or more naturally or non-naturallyoccurring amino acid deletions, insertions or substitutions (e.g., ERBBderivatives, homologs, and fragments), as compared to the amino acidsequence of a native ERBB. The amino acid sequence of an ERBB variant isat least about 80% identical, at least about 90% identical, or at leastabout 95% identical to a native ERBB.

The terms “ERBB-mediated condition, disorder or disease” and “acondition, disorder, or disease mediated by ERBB” refer to a condition,disorder, or disease characterized by abnormal or dysregulated, e.g.,greater than normal, ERBB activity. Abnormal ERBB kinase functionalactivity might arise as the result of ERBB kinase overexpression incells, expression of the ERBB kinase in cells which normally do notexpress ERBB, or dysregulation due to constitutive activation, caused,for example, by a mutation in ERBB. An ERBB-mediated condition,disorder, or disease may be completely or partially mediated byinappropriate ERBB activity. In particular, an ERBB-mediated condition,disorder, or disease is one in which modulation of an ERBB activityresults in some effect on the underlying condition, disorder, ordisease, e.g., an ERBB inhibitor results in some improvement in at leastsome of patients being treated.

The term “alkyl” refers to a linear or branched saturated monovalenthydrocarbon radical, wherein the alkyl may optionally be substitutedwith one or more substituents Q as described herein. For example, C₁₋₆alkyl refers to a linear saturated monovalent hydrocarbon radical of 1to 6 carbon atoms or a branched saturated monovalent hydrocarbon radicalof 3 to 6 carbon atoms. In certain embodiments, the alkyl is a linearsaturated monovalent hydrocarbon radical that has 1 to 20 (C₁₋₂₀), 1 to15 (C₁₋₁₅), 1 to 10 (C₁₋₁₀), or 1 to 6 (C₁₋₆) carbon atoms, or branchedsaturated monovalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15(C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. As used herein,linear C₁₋₆ and branched C₃₋₆ alkyl groups are also referred as “loweralkyl.” Examples of alkyl groups include, but are not limited to,methyl, ethyl, propyl (including all isomeric forms), n-propyl,isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl,sec-butyl, t-butyl, pentyl (including all isomeric forms), and hexyl(including all isomeric forms).

The term “alkylene” refers to a linear or branched saturated divalenthydrocarbon radical, wherein the alkylene may optionally be substitutedwith one or more substituents Q as described herein. For example, C₁₋₆alkylene refers to a linear saturated divalent hydrocarbon radical of 1to 6 carbon atoms or a branched saturated divalent hydrocarbon radicalof 3 to 6 carbon atoms. In certain embodiments, the alkylene is a linearsaturated divalent hydrocarbon radical that has 1 to 20 (C₁₋₂₀), 1 to 15(C₁₋₁₅), 1 to 10 (C₁₋₁₀), or 1 to 6 (C₁₋₆) carbon atoms, or branchedsaturated divalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15(C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. As used herein,linear C₁₋₆ and branched C₃₋₆ alkylene groups are also referred as“lower alkylene.” Examples of alkylene groups include, but are notlimited to, methylene, ethylene, propylene (including all isomericforms), n-propylene, isopropylene, butylene (including all isomericforms), n-butylene, isobutylene, t-butylene, pentylene (including allisomeric forms), and hexylene (including all isomeric forms).

The term “heteroalkylene” refers to a linear or branched saturateddivalent hydrocarbon radical that contains one or more heteroatoms inthe hydrocarbon chain, each of which is independently selected from O,S, and N. For example, C₁₋₆ heteroalkylene refers to a linear saturateddivalent hydrocarbon radical of 1 to 6 carbon atoms or a branchedsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms. Incertain embodiments, the heteroalkylene is a linear saturated divalenthydrocarbon radical that has 1 to 20 (C₁₋₂₀), 1 to 15 (C₁₋₁₅), 1 to 10(C₁₋₁₀), or 1 to 6 (C₁₋₆) carbon atoms, or branched saturated divalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. As used herein, linear C₁₋₆ andbranched C₃₋₆ heteroalkylene groups are also referred as “lowerheteroalkylene.” Examples of heteroalkylene groups include, but are notlimited to, —CH₂O—, —CH₂OCH₂—, —CH₂CH₂O—, —CH₂NH—, —CH₂NHCH₂—,—CH₂CH₂NH—, —CH₂S—, —CH₂SCH₂—, and —CH₂CH₂S—. In certain embodiments,heteroalkylene may also be optionally substituted with one or moresubstituents Q as described herein.

The term “alkenyl” refers to a linear or branched monovalent hydrocarbonradical, which contains one or more, in one embodiment, one, two, three,four, or five, in another embodiment, one or two, carbon-carbon doublebond(s). The alkenyl may be optionally substituted with one or moresubstituents Q as described herein. The term “alkenyl” embraces radicalshaving a “cis” or “trans” configuration or a mixture thereof, oralternatively, a “Z” or “E” configuration or a mixture thereof, asappreciated by those of ordinary skill in the art. For example, C₂₋₆alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbonradical of 3 to 6 carbon atoms. In certain embodiments, the alkenyl is alinear monovalent hydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15(C₂₋₁₅), 2 to 10 (C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branchedmonovalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples of alkenyl groupsinclude, but are not limited to, ethenyl, propen-1-yl, propen-2-yl,allyl, butenyl, and 4-methylbutenyl.

The term “alkenylene” refers to a linear or branched divalenthydrocarbon radical, which contains one or more, in one embodiment, one,two, three, four, or five, in another embodiment, one or two,carbon-carbon double bond(s). The alkenylene may be optionallysubstituted with one or more substituents Q as described herein. Theterm “alkenylene” embraces radicals having a “cis” or “trans”configuration or a mixture thereof, or alternatively, a “Z” or “E”configuration or a mixture thereof, as appreciated by those of ordinaryskill in the art. For example, C₂₋₆ alkenylene refers to a linearunsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or abranched unsaturated divalent hydrocarbon radical of 3 to 6 carbonatoms. In certain embodiments, the alkenylene is a linear divalenthydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10(C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branched divalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples of alkenylene groupsinclude, but are not limited to, ethenylene, allylene, propenylene,butenylene, and 4-methylbutenylene.

The term “heteroalkenylene” refers to a linear or branched divalenthydrocarbon radical, which contains one or more, in one embodiment, one,two, three, four, or five, in another embodiment, one or two,carbon-carbon double bond(s), and which contains one or more heteroatomsin the hydrocarbon chain, each of which is independently selected fromO, S, and N. The heteroalkenylene may be optionally substituted with oneor more substituents Q as described herein. The term “heteroalkenylene”embraces radicals having a “cis” or “trans” configuration or a mixturethereof, or alternatively, a “Z” or “E” configuration or a mixturethereof, as appreciated by those of ordinary skill in the art. Forexample, C₂₋₆ heteroalkenylene refers to a linear unsaturated divalenthydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturateddivalent hydrocarbon radical of 3 to 6 carbon atoms. In certainembodiments, the heteroalkenylene is a linear divalent hydrocarbonradical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10 (C₂₋₁₀), or 2 to 6(C₂₋₆) carbon atoms, or a branched divalent hydrocarbon radical of 3 to20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbonatoms. Examples of heteroalkenylene groups include, but are not limitedto, —CH═CHO—, —CH═CHOCH₂—, —CH═CHCH₂O—, —CH═CHS—, —CH═CHSCH₂—,—CH═CHCH₂S—, or —CH═CHCH₂NH—.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical, which contains one or more, in one embodiment, one, two, three,four, or five, in another embodiment, one or two, carbon-carbon triplebond(s). The alkynyl may be optionally substituted with one or moresubstituents Q as described herein. For example, C₂₋₆ alkynyl refers toa linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbonatoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6carbon atoms. In certain embodiments, the alkynyl is a linear monovalenthydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10(C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branched monovalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples of alkynyl groupsinclude, but are not limited to, ethynyl (—C≡CH), propynyl (includingall isomeric forms, e.g., 1-propynyl (—C≡CCH₃) and propargyl(—CH₂C≡CH)), butynyl (including all isomeric forms, e.g., 1-butyn-1-yland 2-butyn-1-yl), pentynyl (including all isomeric forms, e.g.,1-pentyn-1-yl and 1-methyl-2-butyn-1-yl), and hexynyl (including allisomeric forms, e.g., 1-hexyn-1-yl).

The term “alkynylene” refers to a linear or branched divalenthydrocarbon radical, which contains one or more, in one embodiment, one,two, three, four, or five, in another embodiment, one or two,carbon-carbon triple bond(s). The alkynylene may be optionallysubstituted with one or more substituents Q as described herein. Forexample, C₂₋₆ alkynylene refers to a linear unsaturated divalenthydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturateddivalent hydrocarbon radical of 3 to 6 carbon atoms. In certainembodiments, the alkynylene is a linear divalent hydrocarbon radical of2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10 (C₂₋₁₀), or 2 to 6 (C₂₋₆)carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20(C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbonatoms. Examples of alkynylene groups include, but are not limited to,ethynylene, propynylene (including all isomeric forms, e.g.,1-propynylene and propargylene), butynylene (including all isomericforms, e.g., 1-butyn-1-ylene and 2-butyn-1-ylene), pentynylene(including all isomeric forms, e.g., 1-pentyn-1-ylene and1-methyl-2-butyn-1-ylene), and hexynylene (including all isomeric forms,e.g., 1-hexyn-1-ylene).

The term “cycloalkyl” refers to a cyclic monovalent hydrocarbon radical,which may be optionally substituted with one or more substituents Q asdescribed herein. In one embodiment, cycloalkyl groups may be saturatedor unsaturated but non-aromatic, and/or bridged, and/or non-bridged,and/or fused bicyclic groups. In certain embodiments, the cycloalkyl hasfrom 3 to 20 (C₃₋₂₀), from 3 to 15 (C₃₋₁₅), from 3 to 10 (C₃₋₁₀), orfrom 3 to 7 (C₃₋₇) carbon atoms. Examples of cycloalkyl groups include,but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl,cycloheptenyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, andadamantyl.

The term “cycloalkylene” refers to a cyclic divalent hydrocarbonradical, which may be optionally substituted with one or moresubstituents Q as described herein. In one embodiment, cycloalkyl groupsmay be saturated or unsaturated but non-aromatic, and/or bridged, and/ornon-bridged, and/or fused bicyclic groups. In certain embodiments, thecycloalkylene has from 3 to 20 (C₃₋₂₀), from 3 to 15 (C₃₋₁₅), from 3 to10 (C₃₋₁₀), or from 3 to 7 (C₃₋₇) carbon atoms. Examples ofcycloalkylene groups include, but are not limited to, cyclopropylene(e.g., 1,1-cyclopropylene and 1,2-cyclopropylene), cyclobutylene (e.g.,1,1-cyclobutylene, 1,2-cyclobutylene, or 1,3-cyclobutylene),cyclopentylene (e.g., 1,1-cyclopentylene, 1,2-cyclopentylene, or1,3-cyclopentylene), cyclohexylene (e.g., 1,1-cyclohexylene,1,2-cyclohexylene, 1,3-cyclohexylene, or 1,4-cyclohexylene),cycloheptylene (e.g., 1,1-cycloheptylene, 1,2-cycloheptylene,1,3-cycloheptylene, or 1,4-cycloheptylene), decalinylene, andadamantylene.

The term “aryl” refers to a monovalent monocyclic aromatic hydrocarbonradical or monovalent polycyclic aromatic hydrocarbon radical thatcontains at least one aromatic hydrocarbon ring. In certain embodiments,the aryl has from 6 to 20 (C₆₋₂₀), from 6 to 15 (C₆₋₁₅), or from 6 to 10(C₆₋₁₀) ring atoms. Examples of aryl groups include, but are not limitedto, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl,pyrenyl, biphenyl, and terphenyl. Aryl also refers to bicyclic ortricyclic carbon rings, where one of the rings is aromatic and theothers of which may be saturated, partially unsaturated, or aromatic,for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl(tetralinyl). In certain embodiments, aryl may be optionally substitutedwith one or more substituents Q as described herein.

The term “arylene” refers to a divalent monocyclic aromatic hydrocarbonradical or divalent polycyclic aromatic hydrocarbon radical thatcontains at least one aromatic hydrocarbon ring. In certain embodiments,the arylene has from 6 to 20 (C₆₋₂₀), from 6 to 15 (C₆₋₁₅), or from 6 to10 (C₆₋₁₀) ring atoms. Examples of arylene groups include, but are notlimited to, phenylene, naphthylene, fluorenylene, azulenylene,anthrylene, phenanthrylene, pyrenylene, biphenylene, and terphenylene.Arylene also refers to bicyclic or tricyclic carbon rings, where one ofthe rings is aromatic and the others of which may be saturated,partially unsaturated, or aromatic, for example, dihydronaphthylene,indenylene, indanylene, or tetrahydronaphthylene (tetralinylene). Incertain embodiments, arylene may be optionally substituted with one ormore substituents Q as described herein.

The term “aralkyl” or “arylalkyl” refers to a monovalent alkyl groupsubstituted with one or more aryl groups. In certain embodiments, thearalkyl has from 7 to 30 (C₇₋₃₀), from 7 to 20 (C₇₋₂₀), or from 7 to 16(C₇₋₁₆) carbon atoms. Examples of aralkyl groups include, but are notlimited to, benzyl, 2-phenylethyl, and 3-phenylpropyl. In certainembodiments, aralkyl are optionally substituted with one or moresubstituents Q as described herein.

The term “heteroaryl” refers to a monovalent monocyclic aromatic groupor monovalent polycyclic aromatic group that contains at least onearomatic ring, wherein at least one aromatic ring contains one or moreheteroatoms in the ring, each of which is independently selected from O,S, and N. Heteroaryl groups are bonded to the rest of a molecule throughthe aromatic ring. Each ring of a heteroaryl group can contain one ortwo O atoms, one or two S atoms, and/or one to four N atoms, providedthat the total number of heteroatoms in each ring is four or less andeach ring contains at least one carbon atom. In certain embodiments, theheteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.Examples of monocyclic heteroaryl groups include, but are not limitedto, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl,oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl,triazinyl, and triazolyl. Examples of bicyclic heteroaryl groupsinclude, but are not limited to, benzofuranyl, benzimidazolyl,benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl,benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl,imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl,isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl,isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl,pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl,quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl.Examples of tricyclic heteroaryl groups include, but are not limited to,acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl,phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments,heteroaryl may also be optionally substituted with one or moresubstituents Q as described herein.

The term “heteroarylene” refers to a divalent monocyclic aromatic groupor divalent polycyclic aromatic group that contains at least onearomatic ring, wherein at least one aromatic ring contains one or moreheteroatoms in the ring, each of which is independently selected from O,S, and N. A heteroarylene group has at least one linkage to the rest ofa molecule via its aromatic ring(s). Each ring of a heteroarylene groupcan contain one or two O atoms, one or two S atoms, and/or one to four Natoms, provided that the total number of heteroatoms in each ring isfour or less and each ring contains at least one carbon atom. In certainembodiments, the heteroarylene has from 5 to 20, from 5 to 15, or from 5to 10 ring atoms. Examples of monocyclic heteroarylene groups include,but are not limited to, furanylene, imidazolylene, isothiazolylene,isoxazolylene, oxadiazolylene, oxadiazolylene, oxazolylene,pyrazinylene, pyrazolylene, pyridazinylene, pyridylene, pyrimidinylene,pyrrolylene, thiadiazolylene, thiazolylene, thienylene, tetrazolylene,triazinylene, and triazolylene. Examples of bicyclic heteroarylenegroups include, but are not limited to, benzofuranylene,benzimidazolylene, benzoisoxazolylene, benzopyranylene,benzothiadiazolylene, benzothiazolylene, benzothienylene,benzotriazolylene, benzoxazolylene, furopyridylene, imidazopyridinylene,imidazothiazolylene, indolizinylene, indolylene, indazolylene,isobenzofuranylene, isobenzothienylene, isoindolylene, isoquinolinylene,isothiazolylene, naphthyridinylene, oxazolopyridinylene,phthalazinylene, pteridinylene, purinylene, pyridopyridylene,pyrrolopyridylene, quinolinylene, quinoxalinylene, quinazolinylene,thiadiazolopyrimidylene, and thienopyridylene. Examples of tricyclicheteroarylene groups include, but are not limited to, acridinylene,benzindolylene, carbazolylene, dibenzofuranylene, perimidinylene,phenanthrolinylene, phenanthridinylene, phenarsazinylene, phenazinylene,phenothiazinylene, phenoxazinylene, and xanthenylene. In certainembodiments, heteroarylene may also be optionally substituted with oneor more substituents Q as described herein.

The term “heterocyclyl” or “heterocyclic” refers to a monovalentmonocyclic non-aromatic ring system or monovalent polycyclic ring systemthat contains at least one non-aromatic ring, wherein one or more of thenon-aromatic ring atoms are heteroatoms independently selected from O,S, and N; and the remaining ring atoms are carbon atoms. In certainembodiments, the heterocyclyl or heterocyclic group has from 3 to 20,from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6ring atoms. Heterocyclyl groups are bonded to the rest of a moleculethrough the non-aromatic ring. In certain embodiments, the heterocyclylis a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, whichmay be fused or bridged, and in which nitrogen or sulfur atoms may beoptionally oxidized, nitrogen atoms may be optionally quaternized, andsome rings may be partially or fully saturated, or aromatic. Theheterocyclyl may be attached to the main structure at any heteroatom orcarbon atom which results in the creation of a stable compound. Examplesof such heterocyclic groups include, but are not limited to, azepinyl,benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl,benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl,benzothiopyranyl, benzoxazinyl, β-carbolinyl, chromanyl, chromonyl,cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl,dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl,dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl,furanonyl, imidazolidinyl, imidazolinyl, indolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl,isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl,oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl,pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl,tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl,tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl,and 1,3,5-trithianyl. In certain embodiments, heterocyclic may also beoptionally substituted with one or more substituents Q as describedherein.

The term “heterocyclylene” refers to a divalent monocyclic non-aromaticring system or divalent polycyclic ring system that contains at leastone non-aromatic ring, wherein one or more of the non-aromatic ringatoms are heteroatoms independently selected from O, S, and N; and theremaining ring atoms are carbon atoms. Heterocyclylene groups are bondedto the rest of a molecule through the non-aromatic ring. In certainembodiments, the heterocyclylene group has from 3 to 20, from 3 to 15,from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. Incertain embodiments, the heterocyclylene is a monocyclic, bicyclic,tricyclic, or tetracyclic ring system, which may be fused or bridged,and in which nitrogen or sulfur atoms may be optionally oxidized,nitrogen atoms may be optionally quaternized, and some rings may bepartially or fully saturated, or aromatic. The heterocyclylene may beattached to the main structure at any heteroatom or carbon atom whichresults in the creation of a stable compound. Examples of suchheterocyclylene groups include, but are not limited to, azepinylene,benzodioxanylene, benzodioxolylene, benzofuranonylene,benzopyranonylene, benzopyranylene, benzotetrahydrofuranylene,benzotetrahydrothienylene, benzothiopyranylene, benzoxazinylene,β-carbolinylene, chromanylene, chromonylene, cinnolinylene,coumarinylene, decahydroisoquinolinylene, dihydrobenzisothiazinylene,dihydrobenzisoxazinylene, dihydrofurylene, dihydroisoindolylene,dihydropyranylene, dihydropyrazolylene, dihydropyrazinylene,dihydropyridinylene, dihydropyrimidinylene, dihydropyrrolylene,dioxolanylene, 1,4-dithianylene, furanonylene, imidazolidinylene,imidazolinylene, indolinylene, isobenzotetrahydrofuranylene,isobenzotetrahydrothienylene, isochromanylene, isocoumarinylene,isoindolinylene, isothiazolidinylene, isoxazolidinylene, morpholinylene,octahydroindolylene, octahydroisoindolylene, oxazolidinonylene,oxazolidinylene, oxiranylene, piperazinylene, piperidinylene,4-piperidonylene, pyrazolidinylene, pyrazolinylene, pyrrolidinylene,pyrrolinylene, quinuclidinylene, tetrahydrofurylene,tetrahydroisoquinolinylene, tetrahydropyranylene, tetrahydrothienylene,thiamorpholinylene, thiazolidinylene, tetrahydroquinolinylene, and1,3,5-trithianylene. In certain embodiments, heterocyclic may also beoptionally substituted with one or more substituents Q as describedherein.

The term “halogen”, “halide” or “halo” refers to fluorine, chlorine,bromine, and/or iodine.

The term “optionally substituted” is intended to mean that a group orsubstituent, such as an alkyl, alkylene, heteroalkylene, alkenyl,alkenylene, heteroalkenylene, alkynyl, alkynylene, cycloalkyl,cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene,heterocyclyl, or heterocyclylene group, may be substituted with one ormore, in one embodiment, one, two, three, or four, substituents Q, eachof which is independently selected from, e.g., (a) oxo (═O), cyano(—CN), halo, and nitro (—NO₂); (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl, each of which is further optionally substituted with oneor more, in one embodiment, one, two, three, or four, substituentsQ^(a); and (c) —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),—C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),—OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OP(O)(OR^(a))₂,—OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c),—NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and—S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b), R^(c), and R^(d) isindependently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl,each of which is optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q^(a); or (iii) R^(b)and R^(c) together with the N atom to which they are attached formheterocyclyl, optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q^(a). As usedherein, all groups that can be substituted are “optionally substituted,”unless otherwise specified.

In one embodiment, each Q^(a) is independently selected from the groupconsisting of (a) oxo, cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, and heterocyclyl; and (c) —C(O)R^(f), —C(O)OR^(f),—C(O)NR^(g)R^(h), —C(NR^(f))NR^(g)R^(h), —OR^(f), —OC(O)R^(f),—OC(O)OR^(f), —OC(O)NR^(g)R^(h), —OC(═NR^(f))NR^(g)R^(h),—OP(O)(OR^(f))₂, —OS(O)R^(f), —OS(O)₂R^(f), —OS(O)NR^(g)R^(h),—OS(O)₂NR^(g)R^(h), —NR^(g)R^(h), —NR^(f)C(O)R^(k), —NR^(f)C(O)OR^(k),—NR^(f)C(O)NR^(g)R^(h), —NR^(f)C(═NR^(k))NR^(g)R^(h), —NR^(f)S(O)R^(k),—NR^(f)S(O)₂R^(k), —NR^(f)S(O)NR^(g)R^(h), —NR^(f)S(O)₂NR^(g)R^(h),—SR^(f), —S(O)R^(f), —S(O)₂R^(f), —S(O)NR^(g)R^(h), and—S(O)₂NR^(g)R^(h); wherein each R^(f), R^(g), R^(h), and R^(k) isindependently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl;or (iii) R^(g) and R^(h) together with the N atom to which they areattached form heterocyclyl.

The terms “optically active” and “enantiomerically active” refer to acollection of molecules, which has an enantiomeric excess of no lessthan about 50%, no less than about 70%, no less than about 80%, no lessthan about 90%, no less than about 91%, no less than about 92%, no lessthan about 93%, no less than about 94%, no less than about 95%, no lessthan about 96%, no less than about 97%, no less than about 98%, no lessthan about 99%, no less than about 99.5%, or no less than about 99.8%.In certain embodiments, the compound comprises about 95% or more of oneenantiomer and about 5% or less of the other enantiomer based on thetotal weight of the racemate in question.

In describing an optically active compound, the prefixes R and S areused to denote the absolute configuration of the molecule about itschiral center(s). The (+) and (−) are used to denote the opticalrotation of the compound, that is, the direction in which a plane ofpolarized light is rotated by the optically active compound. The (−)prefix indicates that the compound is levorotatory, that is, thecompound rotates the plane of polarized light to the left orcounterclockwise. The (+) prefix indicates that the compound isdextrorotatory, that is, the compound rotates the plane of polarizedlight to the right or clockwise. However, the sign of optical rotation,(+) and (−), is not related to the absolute configuration of themolecule, R and S.

The term “isotopic variant” refers to a compound that contains anunnatural proportion of an isotope at one or more of the atoms thatconstitute such a compound. In certain embodiments, an “isotopicvariant” of a compound contains unnatural proportions of one or moreisotopes, including, but not limited to, hydrogen (¹H), deuterium (²H),tritium (³H), carbon-11 (¹¹C), carbon-12 (¹²C), carbon-13 (¹³C),carbon-14 (¹⁴C), nitrogen-13 (¹³N), nitrogen-14 (¹⁴N), nitrogen-15(¹⁵N), oxygen-14 (¹⁴O), oxygen-15 (¹⁵O), oxygen-16 (¹⁶O), oxygen-17(¹⁷O), oxygen-18 (¹⁸O), fluorine-17 (¹⁷F), fluorine-18 (¹⁸F),phosphorus-31 (³¹P), phosphorus-32 (³²P), phosphorus-33 (³³P), sulfur-32(³²S), sulfur-33 (³³S), sulfur-34 (³⁴S), sulfur-35 (³⁵S), sulfur-36(³⁶S), chlorine-35 (³⁵Cl), chlorine-36 (³⁶Cl), chlorine-37 (³⁷Cl),bromine-79 (⁷⁹Br), bromine-81 (⁸¹Br), iodine-123 (¹²³I), iodine-125(¹²⁵I), iodine-127 (¹²⁷I), iodine-129 (¹²⁹I), and iodine-131 (¹³¹I). Incertain embodiments, an “isotopic variant” of a compound is in a stableform, that is, non-radioactive. In certain embodiments, an “isotopicvariant” of a compound contains unnatural proportions of one or moreisotopes, including, but not limited to, hydrogen (¹H), deuterium (²H),carbon-12 (¹²C), carbon-13 (¹³C), nitrogen-14 (¹⁴N), nitrogen-15 (¹⁵N),oxygen-16 (¹⁶O), oxygen-17 (¹⁷O), oxygen-18 (¹⁸O), fluorine-17 (¹⁷F),phosphorus-31 (³¹P), sulfur-32 (³²S), sulfur-33 (³³S), sulfur-34 (³⁴S),sulfur-36 (³⁶S), chlorine-35 (³⁵Cl), chlorine-37 (³⁷Cl), bromine-79(⁷⁹Br), bromine-81 (⁸¹Br), and iodine-127 (¹²⁷I). In certainembodiments, an “isotopic variant” of a compound is in an unstable form,that is, radioactive. In certain embodiments, an “isotopic variant” of acompound contains unnatural proportions of one or more isotopes,including, but not limited to, tritium (³H), carbon-11 (¹¹C), carbon-14(¹⁴C), nitrogen-13 (¹³N), oxygen-14 (¹⁴O), oxygen-15 (¹⁵O), fluorine-18(¹⁸F), phosphorus-32 (³²P), phosphorus-33 (³³P), sulfur-35 (³⁵S),chlorine-36 (³⁶Cl), iodine-123 (¹²³I), iodine-125 (¹²⁵I), iodine-129(¹²⁹I), and iodine-131 (¹³¹I). It will be understood that, in a compoundas provided herein, any hydrogen can be ²H, for example, or any carboncan be ¹³C, as example, or any nitrogen can be ¹⁵N, as example, and anyoxygen can be ¹⁸O, where feasible according to the judgment of one ofskill. In certain embodiments, an “isotopic variant” of a compoundcontains unnatural proportions of deuterium.

The term “solvate” refers to a complex or aggregate formed by one ormore molecules of a solute, e.g., a compound provided herein, and one ormore molecules of a solvent, which present in stoichiometric ornon-stoichiometric amount. Suitable solvents include, but are notlimited to, water, methanol, ethanol, n-propanol, isopropanol, andacetic acid. In certain embodiments, the solvent is pharmaceuticallyacceptable. In one embodiment, the complex or aggregate is in acrystalline form. In another embodiment, the complex or aggregate is ina noncrystalline form. Where the solvent is water, the solvate is ahydrate. Examples of hydrates include, but are not limited to, ahemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, andpentahydrate.

The phrase “a single enantiomer, a racemic mixture, a mixture ofdiastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof” has the same meaning asthe phrase “(i) a single enantiomer, a racemic mixture, a mixture ofdiastereomers, or an isotopic variant of the compound referencedtherein; (ii) a pharmaceutically acceptable salt, solvate, or prodrug ofthe compound referenced therein; or (iii) a pharmaceutically acceptablesalt, solvate, or prodrug of a single enantiomer, a racemic mixture, amixture of diastereomers, or an isotopic variant of the compoundreferenced therein.”

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage or recognized abbreviations including abbreviationsfound in J. Org. Chem. 2007, 72, 23A-24A or abbreviations established bythe IUPAC-IUB Commission on Biochemical Nomenclature (Biochem. 1972, 11,942-944).

Compounds

In one embodiment, provided herein is a compound of Formula I:

or a single enantiomer, a racemic mixture, a mixture of diastereomers,or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof;

R¹ is (a) hydrogen, cyano, halo, or nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl,or heterocyclyl; (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); or (d)—C(O)CR^(1e)═CR^(1f)CR^(1g),

—N^(1a)C(O)CR^(1e)═CR^(1f)CR^(1g),

—S(O)CR^(1e)═CR^(1f)CR^(1g),

—S(O₂)CR^(1e)═CR^(1f)CR^(1g),

—NR^(1a)S(O)CR^(1e)═CR^(1f)CR^(1g),

—NR^(1a)S(O₂)CR^(1e)═CR^(1f)CR^(1g), or

R² is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl;

L¹ is a bond, —O—, —S—, —N(R^(1A))—, or —C(R^(1A)R^(1B))—, wherein eachR^(1A) and R^(1B) is independently hydrogen, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl;

L² is C₃₋₁₀ cycloalkylene, C₆₋₁₄ arylene, C₇₋₁₅ aralkylene,heteroarylene, or heterocyclylene;

T is a bond, —O—, —S—, —N═, —N(R⁴)—, or —C(R⁴)═;

U is a bond, —O—, —S—, —N═, —N(R⁵)—, or —C(R⁵)═;

V is a bond, —O—, —S—, —N═, —N(R⁶)—, or —C(R⁶)═;

W is a bond, —O—, —S—, —N═, —N(R⁷)—, or —C(R⁷)═;

X and Y are each independently C or N;

Z is NR^(2A) or CR^(2A)R^(2B), wherein each R^(2A) and R^(2B) isindependently hydrogen, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl;

R⁴, R⁵, R⁶, and R⁷ are each independently (a) hydrogen, cyano, halo, ornitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c)—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); with proviso that at leasttwo of R⁴, R⁵, R⁶, and R⁷ are not hydrogen; and with the proviso that R⁴and R⁵, R⁵ and R⁶, or R⁶ and R⁷ are linked together to form heteroarylor heterocyclyl;

each R^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or R^(1a) and R^(1c) together withthe C and N atoms to which they are attached form heterocyclyl; orR^(1b) and R^(1c) together with the N atom to which they are attachedform heterocyclyl; and

each R^(1e), R^(1f), and R^(1g) is independently hydrogen, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl;

with the proviso that no more than one of T, U, V, and W is a bond;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl,arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl,and heterocyclylene is optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q, where each Q isindependently selected from (a) oxo, cyano, halo, and nitro; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, and heterocyclyl, each of which is furtheroptionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q^(a); and (c) —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c),—OP(O)(OR^(a))₂, —OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c),—OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and—S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b), R^(c), and R^(d) isindependently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl,each of which is optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q^(a); or (iii) R^(b)and R^(c) together with the N atom to which they are attached formheterocyclyl, optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q^(a);

wherein each Q^(a) is independently selected from the group consistingof (a) oxo, cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl; and (c) —C(O)R^(f), —C(O)OR^(f), —C(O)NR^(g)R^(h),—C(NR^(f))NR^(g)R^(h), —OR^(f), —OC(O)R^(f), —OC(O)OR^(f),—OC(O)NR^(g)R^(h), —OC(═NR^(f))NR^(g)R^(h), —OP(O)(OR^(f))₂,—OS(O)R^(f), —OS(O)₂R^(f), —OS(O)NR^(g)R^(h), —OS(O)₂NR^(g)R^(h),—NR^(g)R^(h), —NR^(f)C(O)R^(k), —NR^(f)C(O)OR^(k),—NR^(f)C(O)NR^(g)R^(h), —NR^(f)C(═NR^(k))NR^(g)R^(h), —NR^(f)S(O)R^(k),—NR^(f)S(O)₂R^(k), —NR^(f)S(O)NR^(g)R^(h), —NR^(f)S(O)₂NR^(g)R^(h),—SR^(f), —S(O)R^(f), —S(O)₂R^(f), —S(O)NR^(g)R^(h), and—S(O)₂NR^(g)R^(h); wherein each R^(f), R^(g), R^(h), and R^(k) isindependently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl;or (iii) R^(g) and R^(h) together with the N atom to which they areattached form heterocyclyl.

In another embodiment, provided herein is a compound of Formula II:

or a single enantiomer, a racemic mixture, a mixture of diastereomers,or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof; wherein R¹, R², R⁴, R⁵, R⁶, R⁷, L¹, L², andZ are each as defined herein; and one of the pairs, R⁴ and R⁵, R⁵ andR⁶, and R⁶ and R⁷, are linked together to form C₃₋₇ cycloalkyl, C₆₋₁₄aryl, heteroaryl, or heterocyclyl, each of which is optionallysubstituted with one or more substituents Q.

In yet another embodiment, provided herein is a compound of Formula III:

or a single enantiomer, a racemic mixture, a mixture of diastereomers,or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof; wherein R¹, R², R⁴, R⁵, R⁶, R⁷, L¹, L², andZ are each as defined herein; one of the pairs, R⁴ and R⁵, R⁵ and R⁶,and R⁶ and R⁷, are linked together to form C₃₋₇ cycloalkyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl, each of which is optionally substitutedwith one or more substituents Q; and the symbol

represents that the 6-membered ring contains one N atom in the ring.

In yet another embodiment, provided herein is a compound of Formula IV:

or a single enantiomer, a racemic mixture, a mixture of diastereomers,or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof; wherein:

m is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

n is an integer of 0, 1, 2, 3, 4, 5, or 6;

each R^(L) is independently (i) hydrogen; or (ii) alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl,or heterocyclyl, each of which is optionally substituted with one ormore substituents Q; or (iii) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); or

two R^(L) together, when there are two or more R^(L) attached to thesame ring, are linked together to form (i) a bond, —O—, —NR^(N)—, or—S—; or (ii) C₁₋₆ alkylene, C₁₋₆ heteroalkylene, C₂₋₆ alkenylene, orC₂₋₆ heteroalkenylene, each of which is optionally substituted with oneor more substituents Q;

R^(N) is (a) hydrogen; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl, eachof which is optionally substituted with one or more substituents Q; (c)—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); and

R¹, R², R⁴, R⁵, R⁶, R⁷, R^(1a), R^(1b), R^(1c), R^(1d), and Q is asdefined herein; and one of the pairs, R⁴ and R⁵, R⁵ and R⁶, and R⁶ andR⁷, are linked together to form C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl,or heterocyclyl, each of which is optionally substituted with one ormore substituents Q.

In yet another embodiment, provided herein is a compound of Formula V:

or a single enantiomer, a racemic mixture, a mixture of diastereomers,or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof; wherein R¹, R², R⁴, R⁵, R⁶, and R⁷ are eachas defined herein; and one of the pairs, R⁴ and R⁵, R⁵ and R⁶, and R⁶and R⁷, are linked together to form C₃₋₇ cycloalkyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl, each of which is optionally substitutedwith one or more substituents Q.

In yet another embodiment, provided herein is a compound of Formula VI:

or a single enantiomer, a racemic mixture, a mixture of diastereomers,or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof; wherein R¹, R², R⁴, R⁵, R⁶, and R⁷ are eachas defined herein; and one of the pairs, R⁴ and R⁵, R⁵ and R⁶, and R⁶and R⁷, are linked together to form C₃₋₇ cycloalkyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl, each of which is optionally substitutedwith one or more substituents Q.

In still another embodiment, provided herein is a compound of FormulaVII:

or a single enantiomer, a racemic mixture, a mixture of diastereomers,or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof; wherein R¹, R², R⁴, R⁵, R⁶, and R⁷ are eachas defined herein; and one of the pairs, R⁴ and R⁵, R⁵ and R⁶, and R⁶and R⁷, are linked together to form C₃₋₇ cycloalkyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl, each of which is optionally substitutedwith one or more substituents Q.

In certain embodiments, in Formula I, II, III, IV, V, VI, or VII, R⁵ andR⁶ are linked together to form C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl,or heterocyclyl, each of which is optionally substituted with one ormore substituents Q. In certain embodiments, in Formula I, II, III, IV,V, VI, or VII, R⁵ and R⁶ are linked together to form heterocyclyl,optionally substituted with one or more substituents Q.

In certain embodiments, in Formula I, II, III, IV, V, VI, or VII, R⁵ andR⁶ are linked together to form heterocyclyl selected from:

wherein R^(1a) is as defined herein; and when the heterocyclyl group isnot symmetric, the heterocyclyl group can then be attached to the restof the compound in either direction unless specified.

In certain embodiments, in Formula I, II, III, IV, V, VI, or VII, R⁵ andR⁶ are linked together to form heterocyclyl selected from:

In certain embodiments, in Formula I, II, III, IV, V, VI, or VII, R⁶ andR⁷ are linked together to form C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl,or heterocyclyl, each of which is optionally substituted with one ormore substituents Q. In certain embodiments, in Formula I, II, III, IV,V, VI, or VII, R⁶ and R⁷ are linked together to form heterocyclyl,optionally substituted with one or more substituents Q.

In certain embodiments, in Formula I, II, III, IV, V, VI, or VII, R⁶ andR⁷ are linked together to form heterocyclyl selected from:

wherein p is an integer of 1, 2, 3, 4, 5, or 6; R^(1a) is as definedherein; and when the heterocyclyl group is not symmetric, theheterocyclyl group can then be attached to the rest of the compound ineither directions unless specified.

In certain embodiments, in Formula I, II, III, IV, V, VI, or VII, R⁶ andR⁷ are linked together to form heterocyclyl selected from:

In one embodiment, provided herein is a compound selected from:

and single enantiomers, racemic mixtures, mixtures of diastereomers, andisotopic variants thereof; and pharmaceutically acceptable salts,solvates, and prodrugs thereof; wherein R^(1a) and R^(1f) are each asdefined herein, in one embodiment, R^(1a) is hydrogen or methyl, inanother embodiment, R^(1f) is hydrogen, dimethylaminomethyl,pyrrolidin-1-ylmethyl, or piperidin-1-ylmethyl.

In another embodiment, provided herein is a compound selected from:

and single enantiomers, racemic mixtures, mixtures of diastereomers, andisotopic variants thereof; and pharmaceutically acceptable salts,solvates, and prodrugs thereof; wherein q is an integer of 1, 2, 3, 4,5, or 6; and R^(1a) and R^(1f) are each as defined herein, in oneembodiment, R^(1a) is hydrogen or methyl, in another embodiment, R^(1f)is hydrogen, dimethylaminomethyl, pyrrolidin-1-ylmethyl, orpiperidin-1-ylmethyl.

The groups, R¹, R², R⁴, R⁵, R⁶, R⁷, L¹, L², T, U, V, W, X, Y, Z, m, n,p, q, and r in formulae described herein, including Formulae I to VII,are further defined herein. All combinations of the embodiments providedherein for such groups are within the scope of this disclosure.

In certain embodiments, R¹ is hydrogen. In certain embodiments, R¹ iscyano. In certain embodiments, R¹ is halo. In certain embodiments, R¹ isfluoro, chloro, bromo, or iodo. In certain embodiments, R¹ is fluoro orchloro. In certain embodiments, R¹ is nitro. In certain embodiments, R¹is C₁₋₆ alkyl, optionally substituted with one or more substituents Q.In certain embodiments, R¹ is C₂₋₆ alkenyl, optionally substituted withone or more substituents Q. In certain embodiments, R¹ is C₂₋₆ alkynyl,optionally substituted with one or more substituents Q. In certainembodiments, R¹ is C₃₋₇ cycloalkyl, optionally substituted with one ormore substituents Q. In certain embodiments, R¹ is C₆₋₁₄ aryl,optionally substituted with one or more substituents Q. In certainembodiments, R¹ is C₇₋₁₅ aralkyl, optionally substituted with one ormore substituents Q. In certain embodiments, R¹ is heteroaryl,optionally substituted with one or more substituents Q. In certainembodiments, R¹ is heterocyclyl, optionally substituted with one or moresubstituents Q.

In certain embodiments, R¹ is —C(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R¹ is —C(O)OR^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R¹ is —C(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R¹ is —C(NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b), andR^(1c) are each as defined herein. In certain embodiments, R¹ is—OR^(1a), wherein R^(1a) is as defined herein. In certain embodiments,R¹ is —OC(O)R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R¹ is —OC(O)OR^(1a), wherein R^(1a) is as defined herein.In certain embodiments, R¹ is —OC(O)NR^(1b)R^(1c), wherein R^(1b) andR^(1c) are each as defined herein. In certain embodiments, R¹ is—OC(═NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R¹ is —OS(O)R^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R¹ is—OS(O)₂R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R¹ is —OS(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein. In certain embodiments, R¹ is—OS(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R¹ is —NR^(1b)R^(1c), wherein R^(1b) andR^(1c) are each as defined herein. In certain embodiments, R¹ is—NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R¹ is —NR^(1a)C(O)OR^(1d), whereinR^(1a) and R^(1d) are each as defined herein. In certain embodiments, R¹is —NR^(1a)C(O)NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) areeach as defined herein. In certain embodiments, R¹ is—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), wherein R^(1a), R^(1b), R^(1c) andR^(1d) are each as defined herein. In certain embodiments, R¹ is—NR^(1a)S(O)R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R¹ is —NR^(1a)S(O)₂R^(1d), whereinR^(1a) and R^(1d) are each as defined herein. In certain embodiments, R¹is —NR^(1a)S(O)NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) areeach as defined herein. In certain embodiments, R¹ is—NR^(1a)S(O)₂NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R¹ is —SR^(1a), whereinR^(1a) i s as defined herein. In certain embodiments, R¹ is —S(O)R^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R¹ is—S(O)₂R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R¹ is —S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein. In certain embodiments, R¹ is—S(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein.

In certain embodiments, R¹ is C(O)CR^(1e)═CR^(1f)CR^(1g), whereinR^(1e), R^(1f), and R^(1g) are each as defined herein. In certainembodiments, R¹ is

wherein R^(1e), R^(1f), and R^(1g) are each as defined herein. Incertain embodiments, R¹ is —N^(1a)C(O)CR^(1e)═CR^(1f)CR^(1g), whereinR^(1a), R^(1e), and R^(1g) are each as defined herein. In certainembodiments, R¹ is

wherein R^(1a), R^(1e), R^(1f), and R^(1g) are each as defined herein.In certain embodiments, R¹ is —S(O)CR^(1e)═CR^(1f)CR^(1g), whereinR^(1e), R^(1f), and R^(1g) are each as defined herein. In certainembodiments, R¹ is

wherein R^(1e), R^(1f), and R^(1g) are each as defined herein. Incertain embodiments, R¹ is —NR^(1a)S(O)CR^(1e)═CR^(1f)CR^(1g), whereinR^(1a), R^(1e), R^(1f), and R^(1g) are each as defined herein. Incertain embodiments, R¹ is

wherein R^(1a), R^(1e), R^(1f), and R^(1g) are each as defined herein.In certain embodiments, R¹ is certain embodiments, R¹ is—NR^(1a)S(O₂)CR^(1e)═CR^(1f)CR^(1g), wherein R^(1a), R^(1e), R^(1f), andR^(1g) are each as defined herein. In certain embodiments, R¹ is

wherein R^(1a), R^(1e), R^(1f), and R^(1g) are each as defined herein.In certain embodiments, R^(1a), R^(1e), R^(1f), and R^(1g) are allhydrogen.

In certain embodiments, R¹ is selected from:

In certain embodiments, R¹ is selected from:

In certain embodiments, R² is C₁₋₆ alkyl, optionally substituted withone or more substituents Q. In certain embodiments, R² is C₂₋₆ alkenyl,optionally substituted with one or more substituents Q. In certainembodiments, R² is C₂₋₆ alkynyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R² is C₃₋₇ cycloalkyl,optionally substituted with one or more substituents Q. In certainembodiments, R² is C₆₋₁₄ aryl, optionally substituted with one or moresubstituents Q. In certain embodiments, R² is 6- to 10-memberedmonocyclic or bicyclic aryl, optionally substituted with one or moresubstituents Q. In certain embodiments, R² is phenyl, optionallysubstituted with one or more substituents Q. In certain embodiments, R²is phenyl or methyl-phenyl. In certain embodiments, R2 is phenyl,3-methyl-phenyl, or 4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl. Incertain embodiments, R² is C₇₋₁₅ aralkyl, optionally substituted withone or more substituents Q. In certain embodiments, R² is heteroaryl,optionally substituted with one or more substituents Q. In certainembodiments, R² is 5- to 10-membered heteroaryl, optionally substitutedwith one or more substituents Q. In certain embodiments, R² is 5- to10-membered heteroaryl comprising 1 to 4 hetereoatoms selected from N,O, and S, which is optionally substituted with one or more substituentsQ. In certain embodiments, R² is monocyclic heteroaryl, optionallysubstituted with one or more substituents Q. In certain embodiments, R²is 5-membered heteroaryl, optionally substituted with one or moresubstituents Q. In certain embodiments, R² is 6-membered heteroaryl,optionally substituted with one or more substituents Q. In certainembodiments, R² is pyridinyl or pyridazinyl, optionally substituted withone or more substituents Q. In certain embodiments, R² ismethyl-pyridinyl, methylaminocarbonyl-pyridinyl, or methyl-pyridazinyl.In certain embodiments, R² is 2-methyl-pyridin-4-yl,2-methylaminocarbonyl-pyridin-4-yl, or 3-methyl-pyridazin-5-yl. Incertain embodiments, R2 is hydroxy-pyridinyl, methoxy-pyridinyl,methyl-pyridinyl, difluoromethyl-pyridinyl, trifluoromethyl-pyridinyl,methylaminocarbonyl-pyridinyl, or methyl-pyridazinyl. In certainembodiments, R2 is 2-hydroxy-pyridin-4-yl, 2-methoxy-pyridin-4-yl,2-methyl-pyridin-4-yl, 2-monofluoromethyl-pyridin-4-yl,2-difluoromethyl-pyridin-4-yl, 2-trifluoromethyl-pyridin-4-yl,2-methylaminocarbonyl-pyridin-4-yl, or 3-methyl-pyridazin-5-yl. Incertain embodiments, R² is bicyclic heteroaryl, optionally substitutedwith one or more substituents Q. In certain embodiments, R² is 5,6-fusedheteroaryl, optionally substituted with one or more substituents Q. Incertain embodiments, R² is benzo[c][1,2,5]oxodiazolyl orbenzo[c][1,2,5]thiodiazolyl, each optionally substituted with one ormore substituents Q. In certain embodiments, R² isbenzo[c][1,2,5]oxodiazol-5-yl or benzo[c][1,2,5]thiodiazol-5-yl, eachoptionally substituted with one or more substituents Q. In certainembodiments, R² is heterocyclyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R² is 4- to 12-memberedmonocyclic or bicyclic heterocyclyl comprising 1 to 4 heteroatomsselected from N, O, and S, which is optionally substituted with one ormore substituents Q.

In certain embodiments, R⁴ is hydrogen. In certain embodiments, R⁴ iscyano. In certain embodiments, R⁴ is halo. In certain embodiments, R⁴ isfluoro, chloro, bromo, or iodo. In certain embodiments, R⁴ is nitro. Incertain embodiments, R⁴ is C₁₋₆ alkyl, optionally substituted with oneor more substituents Q. In certain embodiments, R⁴ is C₂₋₆ alkenyl,optionally substituted with one or more substituents Q. In certainembodiments, R⁴ is C₂₋₆ alkynyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R⁴ is C₃₋₇ cycloalkyl,optionally substituted with one or more substituents Q. In certainembodiments, R⁴ is C₆₋₁₄ aryl, optionally substituted with one or moresubstituents Q. In certain embodiments, R⁴ is C₇₋₁₅ aralkyl, optionallysubstituted with one or more substituents Q. In certain embodiments, R⁴is heteroaryl, optionally substituted with one or more substituents Q.In certain embodiments, R⁴ is heterocyclyl, optionally substituted withone or more substituents Q.

In certain embodiments, R⁴ is —C(O)R^(1a), where R^(1a) is as definedherein. In certain embodiments, R⁴ is —C(O)OR^(1a), where R^(1a) is asdefined herein. In certain embodiments, R⁴ is —C(O)NR^(1b)R^(1c), whereR^(1b) and R^(1c) are each as defined herein. In certain embodiments, R⁴is —C(NR^(1a))NR^(1b)R^(1c), where R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R⁴ is —OR^(1a), where R^(1a)is as defined herein. In certain embodiments, R⁴ is —OC(O)R^(1a), whereR^(1a) is as defined herein. In certain embodiments, R⁴ is—OC(O)OR^(1a), where R^(1a) is as defined herein. In certainembodiments, R⁴ is —OC(O)NR^(1b)R^(1c), where R^(1b) and R^(1c) are eachas defined herein. In certain embodiments, R⁴ is—OC(═NR^(1a))NR^(1b)R^(1c), where R^(1a), R^(1b), and R^(1c) are each asdefined herein. In certain embodiments, R⁴ is —OS(O)R^(1a), where R^(1a)is as defined herein. In certain embodiments, R⁴ is —OS(O)₂R^(1a), whereR^(1a) is as defined herein. In certain embodiments, R⁴ is—OS(O)NR^(1b)R^(1c), where R^(1b) and R^(1c) are each as defined herein.In certain embodiments, R⁴ is —OS(O)₂NR^(1b)R^(1c), where R^(1b) andR^(1c) are each as defined herein. In certain embodiments, R⁴ is—NR^(1b)R^(1c), where R^(1b) and R^(1c) are each as defined herein. Incertain embodiments, R⁴ is —NR^(1a)C(O)R^(1d), where R^(1a) and R^(1d)are each as defined herein. In certain embodiments, R⁴ is—NR^(1a)C(O)OR^(1d), where R^(1a) and R^(1d) are each as defined herein.In certain embodiments, R⁴ is —NR^(1a)C(O)NR^(1b)R^(1c), where R^(1a),R^(1b), and R^(1c) are each as defined herein. In certain embodiments,R⁴ is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), where R^(1a), R^(1b), R^(1c),and R^(1d) are each as defined herein. In certain embodiments, R⁴ is—NR^(1a)S(O)R^(1d), where R^(1a) and R^(1d) are each as defined herein.In certain embodiments, R⁴ is —NR^(1a)S(O)₂R^(1d), where R^(1a) andR^(1d) are each defined herein. In certain embodiments, R⁴ is—NR^(1a)S(O)NR^(1b)R^(1c), where R^(1a), R^(1b), and R^(1c) are each asdefined herein. In certain embodiments, R⁴ is—NR^(1a)S(O)₂NR^(1b)R^(1c), where R^(1a), R^(1b), and R^(1c) are each asdefined herein. In certain embodiments, R⁴ is —SR^(1a), where R^(1a) isas defined herein. In certain embodiments, R⁴ is —S(O)R^(1a), whereR^(1a) is as defined herein. In certain embodiments, R⁴ is —S(O)₂R^(1a),where R^(1a) is as defined herein. In certain embodiments, R⁴ is—S(O)NR^(1b)R^(1c), where R^(1b) and R^(1c) are each as defined herein.In certain embodiments, R⁴ is —S(O)₂NR^(1b)R^(1c), where R^(1b) andR^(1c) are each as defined herein. In certain embodiments, two R⁴ arelinked together to form ═O.

In certain embodiments, R⁵ is hydrogen. In certain embodiments, R⁵ iscyano. In certain embodiments, R⁵ is halo. In certain embodiments, R⁵ isfluoro, chloro, bromo, or iodo. In certain embodiments, R⁵ is nitro. Incertain embodiments, R⁵ is C₁₋₆ alkyl, optionally substituted with oneor more substituents Q. In certain embodiments, R⁵ is C₂₋₆ alkenyl,optionally substituted with one or more substituents Q. In certainembodiments, R⁵ is C₂₋₆ alkynyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R⁵ is C₃₋₇ cycloalkyl,optionally substituted with one or more substituents Q. In certainembodiments, R⁵ is C₆₋₁₄ aryl, optionally substituted with one or moresubstituents Q. In certain embodiments, R⁵ is C₇₋₁₅ aralkyl, optionallysubstituted with one or more substituents Q. In certain embodiments, R⁵is heteroaryl, optionally substituted with one or more substituents Q.In certain embodiments, R⁵ is heterocyclyl, optionally substituted withone or more substituents Q. In certain embodiments, R⁵ is piperazinyl,optionally substituted with one or more substituents Q. In certainembodiments, R⁵ is 4-acetylpiperazinyl.

In certain embodiments, R⁵ is —C(O)R^(1a), where R^(1a) is as definedherein. In certain embodiments, R⁵ is —C(O)OR^(1a), where R^(1a) is asdefined herein. In certain embodiments, R⁵ is —C(O)NR^(1b)R^(1c), whereR^(1b) and R^(1c) are each as defined herein. In certain embodiments, R⁵is —C(NR^(1a))NR^(1b)R^(1c), where R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R⁵ is —OR^(1a), where R^(1a)is as defined herein. In certain embodiments, R⁵ is —OC₁₋₆ alkyl,optionally substituted with one or more substituents Q. In certainembodiments, R⁵ is —OCH₃, optionally substituted with one or moresubstituents Q. In certain embodiments, R⁵ is trifluoromethoxy. Incertain embodiments, R⁵ is —O-heterocyclyl, optionally substituted withone or more substituents Q. In certain embodiments, R⁵ is —O-piperidyl,optionally substituted with one or more substituents Q. In certainembodiments, R⁵ is piperid-4-yloxy, optionally substituted with one ormore substituents Q. In certain embodiments, R⁵ is1-ethyl-piperid-4-yloxy. In certain embodiments, R⁵ is —OC(O)R^(1a),where R^(1a) is as defined herein. In certain embodiments, R⁵ is—OC(O)OR^(1a), where R^(1a) is as defined herein. In certainembodiments, R⁵ is —OC(O)NR^(1b)R^(1c), where R^(1b) and R^(1c) are eachas defined herein. In certain embodiments, R⁵ is—OC(═NR^(1a))NR^(1b)R^(1c), where R^(1a), R^(1b), and R^(1c) are each asdefined herein. In certain embodiments, R⁵ is —OS(O)R^(1a), where R^(1a)is as defined herein. In certain embodiments, R⁵ is —OS(O)₂R^(1a), whereR^(1a) is as defined herein. In certain embodiments, R⁵ is—OS(O)NR^(1b)R^(1c), where R^(1b) and R^(1c) are each as defined herein.In certain embodiments, R⁵ is —OS(O)₂NR^(1b)R^(1c), where R^(1b) andR^(1c) are each as defined herein. In certain embodiments, R⁵ is—NR^(1b)R^(1c), where R^(1b) and R^(1c) are each as defined herein. Incertain embodiments, R⁵ is —NR^(1a)C(O)R^(1d), where R^(1a) and R^(1d)are each as defined herein. In certain embodiments, R⁵ is —NHC(O)—C₁₋₆alkyl, optionally substituted with one or more substituents Q. Incertain embodiments, R⁵ is —NHC(O)-methyl, optionally substituted withone or more substituents Q. In certain embodiments, R⁵ is acetamido. Incertain embodiments, R⁵ is —NR^(1a)C(O)OR^(1d), where R^(1a) and R^(1d)are each as defined herein. In certain embodiments, R⁵ is—NR^(1a)C(O)NR^(1b)R^(1c), where R^(1a), R^(1b), and R^(1c) are each asdefined herein. In certain embodiments, R⁵ where—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), where R^(1a), R^(1b), R^(1c), andR^(1d) are each as defined herein. In certain embodiments, R⁵ is—NR^(1a)S(O)R^(1d), where R^(1a) and R^(1d) are each as defined herein.In certain embodiments, R⁵ is —NR^(1a)S(O)₂R^(1d), where R^(1a) andR^(1d) are each defined herein. In certain embodiments, R⁵ is—NR^(1a)S(O)NR^(1b)R^(1c), where R^(1a), R^(1b), and R^(1c) are each asdefined herein. In certain embodiments, R⁵ is—NR^(1a)S(O)₂NR^(1b)R^(1c), where R^(1a), R^(1b), and R^(1c) are each asdefined herein. In certain embodiments, R⁵ is —SR^(1a), where R^(1a) isas defined herein. In certain embodiments, R⁵ is —S(O)R^(1a), whereR^(1a) is as defined herein. In certain embodiments, R⁵ is —S(O)₂R^(1a),where R^(1a) is as defined herein. In certain embodiments, R⁵ is—S(O)NR^(1b)R^(1c), where R^(1b) and R^(1c) are each as defined herein.In certain embodiments, R⁵ is —S(O)₂NR^(1b)R^(1c), where R^(1b) andR^(1c) are each as defined herein. In certain embodiments, two R⁵ arelinked together to form ═O.

In certain embodiments, R⁶ is hydrogen. In certain embodiments, R⁶ iscyano. In certain embodiments, R⁶ is halo. In certain embodiments, R⁶ isfluoro, chloro, bromo, or iodo. In certain embodiments, R⁶ is nitro. Incertain embodiments, R⁶ is C₁₋₆ alkyl, optionally substituted with oneor more substituents Q. In certain embodiments, R⁶ is C₂₋₆ alkenyl,optionally substituted with one or more substituents Q. In certainembodiments, R⁶ is C₂₋₆ alkynyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R⁶ is C₃₋₇ cycloalkyl,optionally substituted with one or more substituents Q. In certainembodiments, R⁶ is C₆₋₁₄ aryl, optionally substituted with one or moresubstituents Q. In certain embodiments, R⁶ is C₇₋₁₅ aralkyl, optionallysubstituted with one or more substituents Q. In certain embodiments, R⁶is heteroaryl, optionally substituted with one or more substituents Q.In certain embodiments, R⁶ is heterocyclyl, optionally substituted withone or more substituents Q.

In certain embodiments, R⁶ is —C(O)R^(1a), where R^(1a) is as definedherein. In certain embodiments, R⁶ is —C(O)OR^(1a), where R^(1a) is asdefined herein. In certain embodiments, R⁶ is —C(O)NR^(1b)R^(1c), whereR^(1b) and R^(1c) are each as defined herein. In certain embodiments, R⁶is —C(NR^(1a))NR^(1b)R^(1c), where R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R⁶ is —OR^(1a), where R^(1a)is as defined herein. In certain embodiments, R⁶ is —O—C₁₋₆ alkyl,optionally substituted with one or more substituents Q. In certainembodiments, R⁶ is —O-ethyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R⁶ is 2-methoxy-ethoxy. Incertain embodiments, R⁶ is —O-heterocyclyl, optionally substituted withone or more substituents Q. In certain embodiments, R⁶ is —O-piperidyl,optionally substituted with one or more substituents Q. In certainembodiments, R⁶ is piperid-4-yloxy, optionally substituted with one ormore substituents Q. In certain embodiments, R⁶ is1-ethyl-piperid-4-yloxy. In certain embodiments, R⁶ is —OC(O)R^(1a),where R^(1a) is as defined herein. In certain embodiments, R⁶ is—OC(O)OR^(1a), where R^(1a) is as defined herein. In certainembodiments, R⁶ is —OC(O)NR^(1b)R^(1c), where R^(1b) and R^(1c) are eachas defined herein. In certain embodiments, R⁶ is—OC(═NR^(1a))NR^(1b)R^(1c), where R^(1a), R^(1b), and R^(1c) are each asdefined herein. In certain embodiments, R⁶ is —OS(O)R^(1a), where R^(1a)is as defined herein. In certain embodiments, R⁶ is —OS(O)₂R^(1a), whereR^(1a) is as defined herein. In certain embodiments, R⁶ is—OS(O)NR^(1b)R^(1c), where R^(1b) and R^(1c) are each as defined herein.In certain embodiments, R⁶ is —OS(O)₂NR^(1b)R^(1c), where R^(1b) andR^(1c) are each as defined herein. In certain embodiments, R⁶ is—NR^(1b)R^(1c), where R^(1b) and R^(1c) are each as defined herein. Incertain embodiments, R⁶ is —NR^(1a)C(O)R^(1d), where R^(1a) and R^(1d)are each as defined herein. In certain embodiments, R⁶ is—NR^(1a)C(O)OR^(1d), where R^(1a) and R^(1d) are each as defined herein.In certain embodiments, R⁶ is —NR^(1a)C(O)NR^(1b)R^(1c), where R^(1a),R^(1b), and R^(1c) are each as defined herein. In certain embodiments,R⁶ is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), where R^(1a), R^(1b), R^(1c),and R^(1d) are each as defined herein. In certain embodiments, R⁶ is—NR^(1a)S(O)R^(1d), where R^(1a) and R^(1d) are each as defined herein.In certain embodiments, R⁶ is —NR^(1a)S(O)₂R^(1d), where R^(1a) andR^(1d) are each defined herein. In certain embodiments, R⁶ is—NR^(1a)S(O)NR^(1b)R^(1c), where R^(1a), R^(1b), and R^(1c) are each asdefined herein. In certain embodiments, R⁶ is—NR^(1a)S(O)₂NR^(1b)R^(1c), where R^(1a), R^(1b), and R^(1c) are each asdefined herein. In certain embodiments, R⁶ is —SR^(1a), where R^(1a) isas defined herein. In certain embodiments, R⁶ is —S(O)R^(1a), whereR^(1a) is as defined herein. In certain embodiments, R⁶ is —S(O)₂R^(1a),where R^(1a) is as defined herein. In certain embodiments, R⁶ is—S(O)NR^(1b)R^(1c), where R^(1b) and R^(1c) are each as defined herein.In certain embodiments, R⁶ is —S(O)₂NR^(1b)R^(1c), where R^(1b) andR^(1c) are each as defined herein. In certain embodiments, two R⁶ arelinked together to form ═O.

In certain embodiments, R⁷ is hydrogen. In certain embodiments, R⁷ iscyano. In certain embodiments, R⁷ is halo. In certain embodiments, R⁷ isfluoro, chloro, bromo, or iodo. In certain embodiments, R⁷ is chloro. Incertain embodiments, R⁷ is bromo. In certain embodiments, R⁷ is nitro.In certain embodiments, R⁷ is C₁₋₆ alkyl, optionally substituted withone or more substituents Q. In certain embodiments, R⁷ is C₂₋₆ alkenyl,optionally substituted with one or more substituents Q. In certainembodiments, R⁷ is C₂₋₆ alkynyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R⁷ is C₃₋₇ cycloalkyl,optionally substituted with one or more substituents Q. In certainembodiments, R⁷ is C₆₋₁₄ aryl, optionally substituted with one or moresubstituents Q. In certain embodiments, R⁷ is C₇₋₁₅ aralkyl, optionallysubstituted with one or more substituents Q. In certain embodiments, R⁷is heteroaryl, optionally substituted with one or more substituents Q.In certain embodiments, R⁷ is heterocyclyl, optionally substituted withone or more substituents Q.

In certain embodiments, R⁷ is —C(O)R^(1a), where R^(1a) is as definedherein. In certain embodiments, R⁷ is —C(O)OR^(1a), where R^(1a) is asdefined herein. In certain embodiments, R⁷ is —C(O)NR^(1b)R^(1c), whereR^(1b) and R^(1c) are each as defined herein. In certain embodiments, R⁷is —C(NR^(1a))NR^(1b)R^(1c), where R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R⁷ is OR^(1a), where R^(1a)is as defined herein. In certain embodiments, R⁷ is —O—C₁₋₆ alkyl,optionally substituted with one or more substituents Q. In certainembodiments, R⁷ is —O-ethyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R⁷ is 2-methoxy-ethoxy. Incertain embodiments, R⁷ is —O-heterocyclyl, optionally substituted withone or more substituents Q. In certain embodiments, R⁷ is —O-piperidyl,optionally substituted with one or more substituents Q. In certainembodiments, R⁷ is piperid-4-yloxy, optionally substituted with one ormore substituents Q. In certain embodiments, R⁶ is1-ethyl-piperid-4-yloxy, 1-acetyl-piperid-4-yloxy, or1-acryloyl-piperid-4-yloxy. In certain embodiments, R⁷ is —OC(O)R^(1a),where R^(1a) is as defined herein. In certain embodiments, R⁷ is—OC(O)OR^(1a), where R^(1a) is as defined herein. In certainembodiments, R⁷ is —OC(O)NR^(1b)R^(1c), where R^(1b) and R^(1c) are eachas defined herein. In certain embodiments, R⁷ is—OC(═NR^(1a))NR^(1b)R^(1c), where R^(1a), R^(1b), and R^(1c) are each asdefined herein. In certain embodiments, R⁷ is —OS(O)R^(1a), where R^(1a)is as defined herein. In certain embodiments, R⁷ is —OS(O)₂R^(1a), whereR^(1a) is as defined herein. In certain embodiments, R⁷ is—OS(O)NR^(1b)R^(1c), where R^(1b) and R^(1c) are each as defined herein.In certain embodiments, R⁷ is —OS(O)₂NR^(1b)R^(1c), where R^(1b) andR^(1c) are each as defined herein. In certain embodiments, R⁷ is—NR^(1b)R^(1c), where R^(1b) and R^(1c) are each as defined herein. Incertain embodiments, R⁷ is —NR^(1a)C(O)R^(1d), where R^(1a) and R^(1d)are each as defined herein. In certain embodiments, R⁷ is—NR^(1a)C(O)OR^(1d), where R^(1a) and R^(1d) are each as defined herein.In certain embodiments, R⁷ is —NR^(1a)C(O)NR^(1b)R^(1c), where R^(1a),R^(1b), and R^(1c) are each as defined herein. In certain embodiments,R⁷ is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), where R^(1a), R^(1b), R^(1c),and R^(1d) are each as defined herein. In certain embodiments, R⁷ is—NR^(1a)S(O)R^(1d), where R^(1a) and R^(1d) are each as defined herein.In certain embodiments, R⁷ is —NR^(1a)S(O)₂R^(1d), where R^(1a) andR^(1d) are each defined herein. In certain embodiments, R⁷ is—NR^(1a)S(O)NR^(1b)R^(1c), where R^(1a), R^(1b), and R^(1c) are each asdefined herein. In certain embodiments, R⁷ is—NR^(1a)S(O)₂NR^(1b)R^(1c), where R^(1a), R^(1b), and R^(1c) are each asdefined herein. In certain embodiments, R⁷ is —SR^(1a), where R^(1a) isas defined herein. In certain embodiments, R⁷ is —S(O)R^(1a), whereR^(1a) is as defined herein. In certain embodiments, R⁷ is —S(O)₂R^(1a),where R^(1a) is as defined herein. In certain embodiments, R⁷ is—S(O)NR^(1b)R^(1c), where R^(1b) and R^(1c) are each as defined herein.In certain embodiments, R⁷ is —S(O)₂NR^(1b)R^(1c), where R^(1b) andR^(1c) are each as defined herein. In certain embodiments, two R⁷ arelinked together to form ═O.

In certain embodiments, one of the pairs, R⁴ and R⁵, R⁵ and R⁶, and R⁶and R⁷, are linked together to form C₃₋₇ cycloalkyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl, each of which is optionally substitutedwith one or more substituents Q.

In certain embodiments, R⁴ and R⁵ are linked together to form C₃₋₇cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q. In certainembodiments, R⁴ and R⁵ are linked together to form C₃₋₇ cycloalkyl,optionally substituted with one or more substituents Q. In certainembodiments, R⁴ and R⁵ are linked together to form C₆₋₁₄ aryl,optionally substituted with one or more substituents Q. In certainembodiments, R⁴ and R⁵ are linked together to form heteroaryl,optionally substituted with one or more substituents Q. In certainembodiments, R⁴ and R⁵ are linked together to form heterocyclyl,optionally substituted with one or more substituents Q.

In certain embodiments, R⁴ and R⁵ are linked together to formheterocyclyl selected from:

wherein p is an integer of 1, 2, 3, 4, 5, or 6; R^(1a) is as definedherein; and when the heterocyclyl group is not symmetric, theheterocyclyl group can then be attached to the rest of the compound ineither directions unless specified.

In certain embodiments, R⁵ and R⁶ are linked together to form C₃₋₇cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q. In certainembodiments, R⁵ and R⁶ are linked together to form C₃₋₇ cycloalkyl,optionally substituted with one or more substituents Q. In certainembodiments, R⁵ and R⁶ are linked together to form C₆₋₁₄ aryl,optionally substituted with one or more substituents Q. In certainembodiments, R⁵ and R⁶ are linked together to form heteroaryl,optionally substituted with one or more substituents Q. In certainembodiments, R⁵ and R⁶ are linked together to form heterocyclyl,optionally substituted with one or more substituents Q.

In certain embodiments, R⁵ and R⁶ are linked together to formheterocyclyl selected from:

wherein p is an integer of 1, 2, 3, 4, 5, or 6; R^(1a) is as definedherein; and when the heterocyclyl group is not symmetric, theheterocyclyl group can then be attached to the rest of the compound ineither directions unless specified.

In certain embodiments, R⁶ and R⁷ are linked together to form C₃₋₇cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q. In certainembodiments, R⁶ and R⁷ are linked together to form C₃₋₇ cycloalkyl,optionally substituted with one or more substituents Q. In certainembodiments, R⁶ and R⁷ are linked together to form C₆₋₁₄ aryl,optionally substituted with one or more substituents Q. In certainembodiments, R⁶ and R⁷ are linked together to form heteroaryl,optionally substituted with one or more substituents Q. In certainembodiments, R⁶ and R⁷ are linked together to form heterocyclyl,optionally substituted with one or more substituents Q.

In certain embodiments, R⁶ and R⁷ are linked together to formheterocyclyl selected from:

wherein p is an integer of 1, 2, 3, 4, 5, or 6; R^(1a) is as definedherein; and when the heterocyclyl group is not symmetric, theheterocyclyl group can then be attached to the rest of the compound ineither directions unless specified.

In certain embodiments, L¹ is a bond. In certain embodiments, L¹ is —O—.In certain embodiments, L¹ is —S—. In certain embodiments, L¹ is—N(R^(1A))—, wherein R^(1A) is as defined herein. In certainembodiments, L¹ is —N(R^(1A))—, wherein R^(1A) is hydrogen or methyl. Incertain embodiments, L¹ is —C(R^(1A)R^(1B))—, wherein R^(1A) and R^(1B)are each as defined herein. In certain embodiments, L¹ is —CH₂—.

In certain embodiments, L² is C₃₋₁₀ cycloalkylene, optionallysubstituted with one or more substituents Q. In certain embodiments, L²is C₆₋₁₄ arylene, optionally substituted with one or more substituentsQ. In certain embodiments, L² is C₇₋₁₅ aralkylene, optionallysubstituted with one or more substituents Q. In certain embodiments, L²is heteroarylene, optionally substituted with one or more substituentsQ. In certain embodiments, L² is heterocyclylene, optionally substitutedwith one or more substituents Q.

In certain embodiments, L² is:

wherein:

s is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

R^(L) and r are each as defined herein.

In certain embodiments, L² is:

wherein s is as defined herein.

In certain embodiments, L² is:

wherein R^(L), r, and s are each as defined herein.

In certain embodiments, L² is:

wherein s is as defined herein.

In certain embodiments, L² is:

wherein:

t is an integer of 0, 1, 2, 3, 4, 5, or 6; and

R^(L) and r are each as defined herein.

In certain embodiments, L² is:

wherein t is as defined herein.

In certain embodiments, L² is:

wherein R^(L), r, and t are each as defined herein.

In certain embodiments, L² is:

wherein t is as defined herein.

In certain embodiments, L¹⁻-L² is:

wherein the symbol

represents that the 6-membered ring contains one to three N atoms in thering, and each sulfur is optionally oxidized as sulfoxide or sulfone.

In certain embodiments, L¹-L² is:

In certain embodiments, T is a bond. In certain embodiments, T is —O—.In certain embodiments, T is S. In certain embodiments, T is —N═. Incertain embodiments, T is —N(R⁴)—, wherein R⁴ is as defined herein. Incertain embodiments, T is —C(R⁴)═, wherein R⁴ is as defined herein. Incertain embodiments, T is —C(R⁴)₂—, wherein R⁴ is as defined herein.

In certain embodiments, U is a bond. In certain embodiments, U is —O—.In certain embodiments, U is —S—. In certain embodiments, U is —N═. Incertain embodiments, U is —N(R⁵)—, wherein R⁵ is as defined herein. Incertain embodiments, U is —C(R⁵)═, wherein R⁵ is as defined herein. Incertain embodiments, U is —C(R⁵)₂—, wherein R⁵ is as defined herein.

In certain embodiments, V is a bond. In certain embodiments, V is —O—.In certain embodiments, V is —S—. In certain embodiments, V is —N═. Incertain embodiments, V is —N(R⁶)—, wherein R⁶ is as defined herein. Incertain embodiments, V is —C(R⁶)═, wherein R⁶ is as defined herein. Incertain embodiments, V is —C(R⁶)₂—, wherein R⁶ is as defined herein.

In certain embodiments, W is a bond. In certain embodiments, W is —O—.In certain embodiments, W is S. In certain embodiments, W is —N═. Incertain embodiments, W is —N(R⁷)—, wherein R⁷ is as defined herein. Incertain embodiments, W is —C(R⁷)═, wherein R⁷ is as defined herein. Incertain embodiments, W is —C(R⁷)₂—, wherein R⁷ is as defined herein.

In certain embodiments, X is C. In certain embodiments, X is N.

In certain embodiments, Y is C. In certain embodiments, Y is N.

In certain embodiments, Z is NR^(2A), wherein R^(2A) is as definedherein. In certain embodiments, Z is NH. In certain embodiments, Z isCR^(2A)R^(2B), wherein R^(2A) and R^(2B) are each as defined herein. Incertain embodiments, Z is CH₂.

In certain embodiments, m is 0. In certain embodiments, m is 1. Incertain embodiments, m is 2. In certain embodiments, m is 3. In certainembodiments, m is 4. In certain embodiments, m is 5. In certainembodiments, m is 6. In certain embodiments, m is 7. In certainembodiments, m is 8. In certain embodiments, m is 9. In certainembodiments, m is 10.

In certain embodiments, n is 0. In certain embodiments, n is 1. Incertain embodiments, n is 2. In certain embodiments, n is 3. In certainembodiments, n is 4. In certain embodiments, n is 5. In certainembodiments, n is 6.

In certain embodiments, p is 0. In certain embodiments, p is 1. Incertain embodiments, p is 2. In certain embodiments, p is 3. In certainembodiments, p is 4. In certain embodiments, p is 5. In certainembodiments, p is 6.

In certain embodiments, q is 0. In certain embodiments, q is 1. Incertain embodiments, q is 2. In certain embodiments, q is 3. In certainembodiments, q is 4. In certain embodiments, q is 5. In certainembodiments, q is 6.

In certain embodiments, r is 0. In certain embodiments, r is 1. Incertain embodiments, r is 2. In certain embodiments, r is 3. In certainembodiments, r is 4. In certain embodiments, r is 5. In certainembodiments, r is 6.

In one embodiment, provided herein is a compound selected from the groupconsisting of:

and isotopic variants thereof and pharmaceutically acceptable salts,solvates, and prodrugs thereof.

In another embodiment, provided herein is a compound selected from thegroup consisting of:

and isotopic variants thereof and pharmaceutically acceptable salts,solvates, and prodrugs thereof.

In yet another embodiment, provided herein is a compound selected fromthe group consisting of:

and isotopic variants thereof and pharmaceutically acceptable salts,solvates, and prodrugs thereof.

The compounds provided herein are intended to encompass all possiblestereoisomers, unless a particular stereochemistry is specified. Wherethe compound provided herein contains an alkenyl or alkenylene group,the compound may exist as one or mixture of geometric cis/trans (or Z/E)isomers. Where structural isomers are interconvertible, the compound mayexist as a single tautomer or a mixture of tautomers. This can take theform of proton tautomerism in the compound that contains, for example,an imino, keto, or oxime group; or so-called valence tautomerism in thecompound that contain an aromatic moiety. It follows that a singlecompound may exhibit more than one type of isomerism.

For example, the compound of Formula I, when Z is NH, may exist in anyof the following tautomeric forms as shown below.

The compounds provided herein may be enantiomerically pure, such as asingle enantiomer or a single diastereomer, or be stereoisomericmixtures, such as a mixture of enantiomers, e.g., a racemic mixture oftwo enantiomers; or a mixture of two or more diastereomers. As such, oneof skill in the art will recognize that administration of a compound inits (R) form is equivalent, for compounds that undergo epimerization invivo, to administration of the compound in its (S) form. Conventionaltechniques for the preparation/isolation of individual enantiomersinclude synthesis from a suitable optically pure precursor, asymmetricsynthesis from achiral starting materials, or resolution of anenantiomeric mixture, for example, chiral chromatography,recrystallization, resolution, diastereomeric salt formation, orderivatization into diastereomeric adducts followed by separation.

When the compound provided herein contains an acidic or basic moiety, itmay also be provided as a pharmaceutically acceptable salt. See, Bergeet al., J. Pharm. Sci. 1977, 66, 1-19; and Handbook of PharmaceuticalSalts, Properties, and Use; Stahl and Wermuth, Ed.; Wiley-VCH and VHCA:Zurich, Switzerland, 2002.

Suitable acids for use in the preparation of pharmaceutically acceptablesalts include, but are not limited to, acetic acid, 2,2-dichloroaceticacid, acylated amino acids, adipic acid, alginic acid, ascorbic acid,L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoicacid, boric acid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid,D-glucuronic acid, L-glutamic acid, α-oxoglutaric acid, glycolic acid,hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid,(+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid,maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid,methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinicacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid,saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid,stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaricacid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, andvaleric acid.

Suitable bases for use in the preparation of pharmaceutically acceptablesalts, including, but not limited to, inorganic bases, such as magnesiumhydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, orsodium hydroxide; and organic bases, such as primary, secondary,tertiary, and quaternary, aliphatic and aromatic amines, includingL-arginine, benethamine, benzathine, choline, deanol, diethanolamine,diethylamine, dimethylamine, dipropylamine, diisopropylamine,2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine,isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine,morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine,piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine,pyridine, quinuclidine, quinoline, isoquinoline, secondary amines,triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

The compound provided herein may also be provided as a prodrug, which isa functional derivative of the compound, for example, of Formula I, IA,or IB and is readily convertible into the parent compound in vivo.Prodrugs are often useful because, in some situations, they may beeasier to administer than the parent compound. They may, for instance,be bioavailable by oral administration whereas the parent compound isnot. The prodrug may also have enhanced solubility in pharmaceuticalcompositions over the parent compound. A prodrug may be converted intothe parent drug by various mechanisms, including enzymatic processes andmetabolic hydrolysis. See, Harper, Progress in Drug Research 1962, 4,221-294; Morozowich et al. in Design of Biopharmaceutical Propertiesthrough Prodrugs and Analogs; Roche Ed., APHA Acad. Pharm. Sci.: 1977;Gangwar et al., Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421;Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39; Farquhar et al., J. Pharm.Sci. 1983, 72, 324-325; Wernuth in Drug Design: Fact or Fantasy; Jolleset al. Eds.; Academic Press: London, 1984; pp 47-72; Design of Prodrugs;Bundgaard et al. Eds.; Elsevier: 1985; Fleisher et al., Methods Enzymol.1985, 112, 360-381; Stella et al., Drugs 1985, 29, 455-473;Bioreversible Carriers in Drug in Drug Design, Theory and Application;Roche Ed.; APHA Acad. Pharm. Sci.: 1987; Bundgaard, Controlled DrugDelivery 1987, 17, 179-96; Waller et al., Br. J. Clin. Pharmac. 1989,28, 497-507; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15,143-53; Freeman et al., J. Chem. Soc., Chem. Commun. 1991, 875-877;Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; Nathwani and Wood,Drugs 1993, 45, 866-94; Friis and Bundgaard, Eur. J. Pharm. Sci. 1996,4, 49-59; Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115-130;Sinhababu and Thakker, Adv. Drug Delivery Rev. 1996, 19, 241-273;Taylor, Adv. Drug Delivery Rev. 1996, 19, 131-148; Gaignault et al.,Pract. Med. Chem. 1996, 671-696; Browne, Clin. Neuropharmacol. 1997, 20,1-12; Valentino and Borchardt, Drug Discovery Today 1997, 2, 148-155;Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen etal., Pharm. Biotech. 1998, 11, 345-365; Wiebe and Knaus, Adv. DrugDelivery Rev. 1999, 39, 63-80; Tan et al., Adv. Drug Delivery Rev. 1999,39, 117-151; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39,183-209; Wang et al., Curr. Pharm. Design 1999, 5, 265-287; Han et al.,AAPS Pharmsci. 2000, 2, 1-11; Asgharnejad in Transport Processes inPharmaceutical Systems; Amidon et al., Eds.; Marcell Dekker: 2000; pp185-218; Sinha et al., Pharm. Res. 2001, 18, 557-564; Anand et al.,Expert Opin. Biol. Ther. 2002, 2, 607-620; Rao, Resonace 2003, 19-27;Sloan et al., Med. Res. Rev. 2003, 23, 763-793; Patterson et al., Curr.Pharm. Des. 2003, 9, 2131-2154; Hu, IDrugs 2004, 7, 736-742; Robinson etal., Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 14527-14532; Erion et al.,J. Pharmacol. Exp. Ther. 2005, 312, 554-560; Fang et al., Curr. DrugDiscov. Technol. 2006, 3, 211-224; Stanczak et al., Pharmacol. Rep.2006, 58, 599-613; Sloan et al., Pharm. Res. 2006, 23, 2729-2747; Stellaet al., Adv. Drug Deliv. Rev. 2007, 59, 677-694; Gomes et al., Molecules2007, 12, 2484-2506; Krafz et al., ChemMedChem 2008, 3, 20-53; Rautio etal., AAPS J. 2008, 10, 92-102; Rautio et al., Nat. Rev. Drug. Discov.2008, 7, 255-270; Pavan et al., Molecules, 2008, 13, 1035-1065; Sandroset al., Molecules 2008, 13, 1156-1178; Singh et al., Curr. Med. Chem.2008, 15, 1802-1826; Onishi et al., Molecules, 2008, 13, 2136-2155;Huttunen et al., Curr. Med. Chem. 2008, 15, 2346-2365; and Serafin etal., Mini Rev. Med. Chem. 2009, 9, 481-497.

Methods of Synthesis

The compounds provided herein can be prepared, isolated, or obtained byany method known to one of skill in the art. For an example, a compoundof Formula I can be prepared as shown in Scheme I.

Compound I-1 is treated with nucleophilic amine I-2 to form compoundI-3, wherein X¹ is a leaving group, including, but not limited tofluoro, chloro, bromo, methoxy, ethoxy, and nitro. The nitro group ofcompound I-3 is reduced with a reducing agent, e.g., zinc, FeCl₂, NiCl₂,or Na₂S₂O₃, to form compound I-4. The reduction can also be accomplishedvia hydrogenation using, e.g., ammonium formate or hydrogen in thepresence of Pd/C. Compound I-5 is then cyclized to form compound I-5with the Z group installed simultaneously. When Z is NH, compound I-5 isthen coupled with an acid (R²COOH) using a coupling reagent, e.g., HATU,HBTU, PyBroP, PyBOP, or EDCI, to form compound of Formula I.

Pharmaceutical Compositions

Provided herein are pharmaceutical compositions comprising a compoundprovided herein, e.g., a compound of Formula I, as an active ingredient,including a single enantiomer, a racemic mixture, a mixture ofdiastereomers, or an isotopic variant thereof or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof and a pharmaceuticallyacceptable vehicle, carrier, diluent, or excipient, or a mixturethereof.

Suitable excipients are well known to those skilled in the art, andnon-limiting examples of suitable excipients are provided herein.Whether a particular excipient is suitable for incorporation into apharmaceutical composition or dosage form depends on a variety offactors well known in the art, including, but not limited to, the methodof administration. For example, oral dosage forms such as tablets maycontain excipients not suited for use in parenteral dosage forms. Thesuitability of a particular excipient may also depend on the specificactive ingredients in the dosage form. For example, the decomposition ofsome active ingredients may be accelerated by some excipients such aslactose, or when exposed to water. Active ingredients that compriseprimary or secondary amines are particularly susceptible to suchaccelerated decomposition. Consequently, provided herein arepharmaceutical compositions and dosage forms that contain little, ifany, lactose, or other mono- or di-saccharides. As used herein, the term“lactose-free” means that the amount of lactose present, if any, isinsufficient to substantially increase the degradation rate of an activeingredient.

The compound provided herein may be administered alone, or incombination with one or more other compounds provided herein. Thepharmaceutical compositions that comprise a compound provided herein,e.g., a compound of Formula I, or a single enantiomer, a racemicmixture, a mixture of diastereomers, or an isotopic variant thereof; ora pharmaceutically acceptable salt, solvate, or prodrug thereof, can beformulated in various dosage forms for oral, parenteral, and topicaladministration. The pharmaceutical compositions can also be formulatedas modified release dosage forms, including delayed-, extended-,prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-,targeted-, programmed-release, and gastric retention dosage forms. Thesedosage forms can be prepared according to conventional methods andtechniques known to those skilled in the art (see, Remington: TheScience and Practice of Pharmacy, supra; Modified-Release Drug DeliveryTechnology, 2nd ed.; Rathbone et al., Eds.; Marcel Dekker, Inc.: NewYork, N.Y., 2008).

In one embodiment, the pharmaceutical compositions are provided in adosage form for oral administration, which comprise a compound providedherein, e.g., a compound of Formula I, or a single enantiomer, a racemicmixture, a mixture of diastereomers, or an isotopic variant thereof; ora pharmaceutically acceptable salt, solvate, or prodrug thereof; and apharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, the pharmaceutical compositions are provided in adosage form for parenteral administration, which comprise a compoundprovided herein, e.g., a compound of Formula I, or a single enantiomer,a racemic mixture, a mixture of diastereomers, or an isotopic variantthereof; or a pharmaceutically acceptable salt, solvate, or prodrugthereof; and a pharmaceutically acceptable salt, solvate, or prodrugthereof.

In yet another embodiment, the pharmaceutical compositions are providedin a dosage form for topical administration, which comprise a compoundprovided herein, e.g., a compound of Formula I, or a single enantiomer,a racemic mixture, a mixture of diastereomers, or an isotopic variantthereof; or a pharmaceutically acceptable salt, solvate, or prodrugthereof; and a pharmaceutically acceptable salt, solvate, or prodrugthereof.

The pharmaceutical compositions provided herein can be provided in aunit-dosage form or multiple-dosage form. A unit-dosage form, as usedherein, refers to physically discrete a unit suitable for administrationto a human and animal subject, and packaged individually as is known inthe art. Each unit-dose contains a predetermined quantity of an activeingredient(s) sufficient to produce the desired therapeutic effect, inassociation with the required pharmaceutical carriers or excipients.Examples of a unit-dosage form include an ampoule, syringe, andindividually packaged tablet and capsule. For example, a 100 mg unitdose contains about 100 mg of an active ingredient in a packaged tabletor capsule. A unit-dosage form may be administered in fractions ormultiples thereof. A multiple-dosage form is a plurality of identicalunit-dosage forms packaged in a single container to be administered insegregated unit-dosage form. Examples of a multiple-dosage form includea vial, bottle of tablets or capsules, or bottle of pints or gallons.

The pharmaceutical compositions provided herein can be administered atonce, or multiple times at intervals of time. It is understood that theprecise dosage and duration of treatment may vary with the age, weight,and condition of the patient being treated, and may be determinedempirically using known testing protocols or by extrapolation from invivo or in vitro test or diagnostic data. It is further understood thatfor any particular individual, specific dosage regimens should beadjusted over time according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the formulations.

A. Oral Administration

The pharmaceutical compositions provided herein for oral administrationcan be provided in solid, semisolid, or liquid dosage forms for oraladministration. As used herein, oral administration also includesbuccal, lingual, and sublingual administration. Suitable oral dosageforms include, but are not limited to, tablets, fastmelts, chewabletablets, capsules, pills, strips, troches, lozenges, pastilles, cachets,pellets, medicated chewing gum, bulk powders, effervescent ornon-effervescent powders or granules, oral mists, solutions, emulsions,suspensions, wafers, sprinkles, elixirs, and syrups. In addition to theactive ingredient(s), the pharmaceutical compositions can contain one ormore pharmaceutically acceptable carriers or excipients, including, butnot limited to, binders, fillers, diluents, disintegrants, wettingagents, lubricants, glidants, coloring agents, dye-migration inhibitors,sweetening agents, flavoring agents, emulsifying agents, suspending anddispersing agents, preservatives, solvents, non-aqueous liquids, organicacids, and sources of carbon dioxide.

Binders or granulators impart cohesiveness to a tablet to ensure thetablet remaining intact after compression. Suitable binders orgranulators include, but are not limited to, starches, such as cornstarch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500);gelatin; sugars, such as sucrose, glucose, dextrose, molasses, andlactose; natural and synthetic gums, such as acacia, alginic acid,alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage ofisabgol husks, carboxymethylcellulose, methylcellulose,polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powderedtragacanth, and guar gum; celluloses, such as ethyl cellulose, celluloseacetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxyethylcellulose (HEC),hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC);microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103,AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixturesthereof. Suitable fillers include, but are not limited to, talc, calciumcarbonate, microcrystalline cellulose, powdered cellulose, dextrates,kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinizedstarch, and mixtures thereof. The amount of a binder or filler in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The binder or filler may be present from about 50 to about 99%by weight in the pharmaceutical compositions provided herein.

Suitable diluents include, but are not limited to, dicalcium phosphate,calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose,kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.Certain diluents, such as mannitol, lactose, sorbitol, sucrose, andinositol, when present in sufficient quantity, can impart properties tosome compressed tablets that permit disintegration in the mouth bychewing. Such compressed tablets can be used as chewable tablets. Theamount of a diluent in the pharmaceutical compositions provided hereinvaries upon the type of formulation, and is readily discernible to thoseof ordinary skill in the art.

Suitable disintegrants include, but are not limited to, agar; bentonite;celluloses, such as methylcellulose and carboxymethylcellulose; woodproducts; natural sponge; cation-exchange resins; alginic acid; gums,such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses,such as croscarmellose; cross-linked polymers, such as crospovidone;cross-linked starches; calcium carbonate; microcrystalline cellulose,such as sodium starch glycolate; polacrilin potassium; starches, such ascorn starch, potato starch, tapioca starch, and pre-gelatinized starch;clays; aligns; and mixtures thereof. The amount of a disintegrant in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The amount of a disintegrant in the pharmaceutical compositionsprovided herein varies upon the type of formulation, and is readilydiscernible to those of ordinary skill in the art. The pharmaceuticalcompositions provided herein may contain from about 0.5 to about 15% orfrom about 1 to about 5% by weight of a disintegrant.

Suitable lubricants include, but are not limited to, calcium stearate;magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol;mannitol; glycols, such as glycerol behenate and polyethylene glycol(PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetableoil, including peanut oil, cottonseed oil, sunflower oil, sesame oil,olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyllaureate; agar; starch; lycopodium; silica or silica gels, such asAEROSIL® 200 (W.R. Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co.of Boston, Mass.); and mixtures thereof. The pharmaceutical compositionsprovided herein may contain about 0.1 to about 5% by weight of alubricant.

Suitable glidants include, but are not limited to, colloidal silicondioxide, CAB-O-SIL® (Cabot Co. of Boston, Mass.), and asbestos-freetalc. Suitable coloring agents include, but are not limited to, any ofthe approved, certified, water soluble FD&C dyes, and water insolubleFD&C dyes suspended on alumina hydrate, and color lakes and mixturesthereof. A color lake is the combination by adsorption of awater-soluble dye to a hydrous oxide of a heavy metal, resulting in aninsoluble form of the dye. Suitable flavoring agents include, but arenot limited to, natural flavors extracted from plants, such as fruits,and synthetic blends of compounds which produce a pleasant tastesensation, such as peppermint and methyl salicylate. Suitable sweeteningagents include, but are not limited to, sucrose, lactose, mannitol,syrups, glycerin, and artificial sweeteners, such as saccharin andaspartame. Suitable emulsifying agents include, but are not limited to,gelatin, acacia, tragacanth, bentonite, and surfactants, such aspolyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylenesorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suitablesuspending and dispersing agents include, but are not limited to, sodiumcarboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodiumcarbomethylcellulose, hydroxypropyl methylcellulose, andpolyvinylpyrrolidone. Suitable preservatives include, but are notlimited to, glycerin, methyl and propylparaben, benzoic add, sodiumbenzoate and alcohol. Suitable wetting agents include, but are notlimited to, propylene glycol monostearate, sorbitan monooleate,diethylene glycol monolaurate, and polyoxyethylene lauryl ether.Suitable solvents include, but are not limited to, glycerin, sorbitol,ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized inemulsions include, but are not limited to, mineral oil and cottonseedoil. Suitable organic acids include, but are not limited to, citric andtartaric acid. Suitable sources of carbon dioxide include, but are notlimited to, sodium bicarbonate and sodium carbonate.

It should be understood that many carriers and excipients may serve aplurality of functions, even within the same formulation.

The pharmaceutical compositions provided herein for oral administrationcan be provided as compressed tablets, tablet triturates, chewablelozenges, rapidly dissolving tablets, multiple compressed tablets, orenteric-coating tablets, sugar-coated, or film-coated tablets.Enteric-coated tablets are compressed tablets coated with substancesthat resist the action of stomach acid but dissolve or disintegrate inthe intestine, thus protecting the active ingredients from the acidicenvironment of the stomach. Enteric-coatings include, but are notlimited to, fatty acids, fats, phenyl salicylate, waxes, shellac,ammoniated shellac, and cellulose acetate phthalates. Sugar-coatedtablets are compressed tablets surrounded by a sugar coating, which maybe beneficial in covering up objectionable tastes or odors and inprotecting the tablets from oxidation. Film-coated tablets arecompressed tablets that are covered with a thin layer or film of awater-soluble material. Film coatings include, but are not limited to,hydroxyethylcellulose, sodium carboxymethylcellulose, polyethyleneglycol 4000, and cellulose acetate phthalate. Film coating imparts thesame general characteristics as sugar coating. Multiple compressedtablets are compressed tablets made by more than one compression cycle,including layered tablets, and press-coated or dry-coated tablets.

The tablet dosage forms can be prepared from the active ingredient inpowdered, crystalline, or granular forms, alone or in combination withone or more carriers or excipients described herein, including binders,disintegrants, controlled-release polymers, lubricants, diluents, and/orcolorants. Flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

The pharmaceutical compositions provided herein for oral administrationcan be provided as soft or hard capsules, which can be made fromgelatin, methylcellulose, starch, or calcium alginate. The hard gelatincapsule, also known as the dry-filled capsule (DFC), consists of twosections, one slipping over the other, thus completely enclosing theactive ingredient. The soft elastic capsule (SEC) is a soft, globularshell, such as a gelatin shell, which is plasticized by the addition ofglycerin, sorbitol, or a similar polyol. The soft gelatin shells maycontain a preservative to prevent the growth of microorganisms. Suitablepreservatives are those as described herein, including methyl- andpropyl-parabens, and sorbic acid. The liquid, semisolid, and soliddosage forms provided herein may be encapsulated in a capsule. Suitableliquid and semisolid dosage forms include solutions and suspensions inpropylene carbonate, vegetable oils, or triglycerides. Capsulescontaining such solutions can be prepared as described in U.S. Pat. Nos.4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient.

The pharmaceutical compositions provided herein for oral administrationcan be provided in liquid and semisolid dosage forms, includingemulsions, solutions, suspensions, elixirs, and syrups. An emulsion is atwo-phase system, in which one liquid is dispersed in the form of smallglobules throughout another liquid, which can be oil-in-water orwater-in-oil. Emulsions may include a pharmaceutically acceptablenon-aqueous liquid or solvent, emulsifying agent, and preservative.Suspensions may include a pharmaceutically acceptable suspending agentand preservative. Aqueous alcoholic solutions may include apharmaceutically acceptable acetal, such as a di(lower alkyl) acetal ofa lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and awater-miscible solvent having one or more hydroxyl groups, such aspropylene glycol and ethanol. Elixirs are clear, sweetened, andhydroalcoholic solutions. Syrups are concentrated aqueous solutions of asugar, for example, sucrose, and may also contain a preservative. For aliquid dosage form, for example, a solution in a polyethylene glycol maybe diluted with a sufficient quantity of a pharmaceutically acceptableliquid carrier, e.g., water, to be measured conveniently foradministration.

Other useful liquid and semisolid dosage forms include, but are notlimited to, those containing the active ingredient(s) provided herein,and a dialkylated mono- or poly-alkylene glycol, including,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 referto the approximate average molecular weight of the polyethylene glycol.These formulations can further comprise one or more antioxidants, suchas butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, bisulfite, sodium metabisulfite, thiodipropionic acid and itsesters, and dithiocarbamates.

The pharmaceutical compositions provided herein for oral administrationcan be also provided in the forms of liposomes, micelles, microspheres,or nanosystems. Micellar dosage forms can be prepared as described inU.S. Pat. No. 6,350,458.

The pharmaceutical compositions provided herein for oral administrationcan be provided as non-effervescent or effervescent, granules andpowders, to be reconstituted into a liquid dosage form. Pharmaceuticallyacceptable carriers and excipients used in the non-effervescent granulesor powders may include diluents, sweeteners, and wetting agents.Pharmaceutically acceptable carriers and excipients used in theeffervescent granules or powders may include organic acids and a sourceof carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosageforms.

The pharmaceutical compositions provided herein for oral administrationcan be formulated as immediate or modified release dosage forms,including delayed-, sustained, pulsed-, controlled, targeted-, andprogrammed-release forms.

B. Parenteral Administration

The pharmaceutical compositions provided herein can be administeredparenterally by injection, infusion, or implantation, for local orsystemic administration. Parenteral administration, as used herein,include intravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular, intrasynovial, intravesical, and subcutaneousadministration.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated in any dosage forms that are suitablefor parenteral administration, including solutions, suspensions,emulsions, micelles, liposomes, microspheres, nanosystems, and solidforms suitable for solutions or suspensions in liquid prior toinjection. Such dosage forms can be prepared according to conventionalmethods known to those skilled in the art of pharmaceutical science(see, Remington: The Science and Practice of Pharmacy, supra).

The pharmaceutical compositions intended for parenteral administrationcan include one or more pharmaceutically acceptable carriers andexcipients, including, but not limited to, aqueous vehicles,water-miscible vehicles, non-aqueous vehicles, antimicrobial agents orpreservatives against the growth of microorganisms, stabilizers,solubility enhancers, isotonic agents, buffering agents, antioxidants,local anesthetics, suspending and dispersing agents, wetting oremulsifying agents, complexing agents, sequestering or chelating agents,cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents,and inert gases.

Suitable aqueous vehicles include, but are not limited to, water,saline, physiological saline or phosphate buffered saline (PBS), sodiumchloride injection, Ringers injection, isotonic dextrose injection,sterile water injection, dextrose and lactated Ringers injection.Suitable non-aqueous vehicles include, but are not limited to, fixedoils of vegetable origin, castor oil, corn oil, cottonseed oil, oliveoil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil,hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chaintriglycerides of coconut oil, and palm seed oil. Suitable water-misciblevehicles include, but are not limited to, ethanol, 1,3-butanediol,liquid polyethylene glycol (e.g., polyethylene glycol 300 andpolyethylene glycol 400), propylene glycol, glycerin,N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

Suitable antimicrobial agents or preservatives include, but are notlimited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol,methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride(e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbicacid. Suitable isotonic agents include, but are not limited to, sodiumchloride, glycerin, and dextrose. Suitable buffering agents include, butare not limited to, phosphate and citrate. Suitable antioxidants arethose as described herein, including bisulfite and sodium metabisulfite.Suitable local anesthetics include, but are not limited to, procainehydrochloride. Suitable suspending and dispersing agents are those asdescribed herein, including sodium carboxymethylcelluose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agentsare those described herein, including polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamineoleate. Suitable sequestering or chelating agents include, but are notlimited to EDTA. Suitable pH adjusting agents include, but are notlimited to, sodium hydroxide, hydrochloric acid, citric acid, and lacticacid. Suitable complexing agents include, but are not limited to,cyclodextrins, including α-cyclodextrin, β-cyclodextrin,hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, andsulfobutylether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

When the pharmaceutical compositions provided herein are formulated formultiple dosage administration, the multiple dosage parenteralformulations must contain an antimicrobial agent at bacteriostatic orfungistatic concentrations. All parenteral formulations must be sterile,as known and practiced in the art.

In one embodiment, the pharmaceutical compositions for parenteraladministration are provided as ready-to-use sterile solutions. Inanother embodiment, the pharmaceutical compositions are provided assterile dry soluble products, including lyophilized powders andhypodermic tablets, to be reconstituted with a vehicle prior to use. Inyet another embodiment, the pharmaceutical compositions are provided asready-to-use sterile suspensions. In yet another embodiment, thepharmaceutical compositions are provided as sterile dry insolubleproducts to be reconstituted with a vehicle prior to use. In stillanother embodiment, the pharmaceutical compositions are provided asready-to-use sterile emulsions.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated as immediate or modified release dosageforms, including delayed-, sustained, pulsed-, controlled, targeted-,and programmed-release forms.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated as a suspension, solid, semi-solid, orthixotropic liquid, for administration as an implanted depot. In oneembodiment, the pharmaceutical compositions provided herein aredispersed in a solid inner matrix, which is surrounded by an outerpolymeric membrane that is insoluble in body fluids but allows theactive ingredient in the pharmaceutical compositions diffuse through.

Suitable inner matrixes include, but are not limited to,polymethylmethacrylate, polybutyl-methacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethylene terephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers, such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinyl alcohol, andcross-linked partially hydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include but are not limited to,polyethylene, polypropylene, ethylene/propylene copolymers,ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers,silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinatedpolyethylene, polyvinylchloride, vinyl chloride copolymers with vinylacetate, vinylidene chloride, ethylene and propylene, ionomerpolyethylene terephthalate, butyl rubber epichlorohydrin rubbers,ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcoholterpolymer, and ethylene/vinyloxyethanol copolymer.

C. Topical Administration

The pharmaceutical compositions provided herein can be administeredtopically to the skin, orifices, or mucosa. The topical administration,as used herein, includes (intra)dermal, conjunctival, intracorneal,intraocular, ophthalmic, auricular, transdermal, nasal, vaginal,urethral, respiratory, and rectal administration.

The pharmaceutical compositions provided herein can be formulated in anydosage forms that are suitable for topical administration for local orsystemic effect, including emulsions, solutions, suspensions, creams,gels, hydrogels, ointments, dusting powders, dressings, elixirs,lotions, suspensions, tinctures, pastes, foams, films, aerosols,irrigations, sprays, suppositories, bandages, and dermal patches. Thetopical formulation of the pharmaceutical compositions provided hereincan also comprise liposomes, micelles, microspheres, nanosystems, andmixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use inthe topical formulations provided herein include, but are not limitedto, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles,antimicrobial agents or preservatives against the growth ofmicroorganisms, stabilizers, solubility enhancers, isotonic agents,buffering agents, antioxidants, local anesthetics, suspending anddispersing agents, wetting or emulsifying agents, complexing agents,sequestering or chelating agents, penetration enhancers,cryoprotectants, lyoprotectants, thickening agents, and inert gases.

The pharmaceutical compositions can also be administered topically byelectroporation, iontophoresis, phonophoresis, sonophoresis, ormicroneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp.,Emeryville, Calif.), and BIOJECT™ (Bioject Medical Technologies Inc.,Tualatin, Oreg.).

The pharmaceutical compositions provided herein can be provided in theforms of ointments, creams, and gels. Suitable ointment vehicles includeoleaginous or hydrocarbon vehicles, including lard, benzoinated lard,olive oil, cottonseed oil, and other oils, white petrolatum;emulsifiable or absorption vehicles, such as hydrophilic petrolatum,hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles,such as hydrophilic ointment; water-soluble ointment vehicles, includingpolyethylene glycols of varying molecular weight; emulsion vehicles,either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions,including cetyl alcohol, glyceryl monostearate, lanolin, and stearicacid (see, Remington: The Science and Practice of Pharmacy, supra).These vehicles are emollient but generally require addition ofantioxidants and preservatives.

Suitable cream base can be oil-in-water or water-in-oil. Suitable creamvehicles may be water-washable, and contain an oil phase, an emulsifier,and an aqueous phase. The oil phase is also called the “internal” phase,which is generally comprised of petrolatum and a fatty alcohol such ascetyl or stearyl alcohol. The aqueous phase usually, although notnecessarily, exceeds the oil phase in volume, and generally contains ahumectant. The emulsifier in a cream formulation may be a nonionic,anionic, cationic, or amphoteric surfactant.

Gels are semisolid, suspension-type systems. Single-phase gels containorganic macromolecules distributed substantially uniformly throughoutthe liquid carrier. Suitable gelling agents include, but are not limitedto, crosslinked acrylic acid polymers, such as carbomers,carboxypolyalkylenes, and CARBOPOL®; hydrophilic polymers, such aspolyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, andpolyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose,hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylmethylcellulose phthalate, and methylcellulose; gums, such as tragacanthand xanthan gum; sodium alginate; and gelatin. In order to prepare auniform gel, dispersing agents such as alcohol or glycerin can be added,or the gelling agent can be dispersed by trituration, mechanical mixing,and/or stirring.

The pharmaceutical compositions provided herein can be administeredrectally, urethrally, vaginally, or perivaginally in the forms ofsuppositories, pessaries, bougies, poultices or cataplasm, pastes,powders, dressings, creams, plasters, contraceptives, ointments,solutions, emulsions, suspensions, tampons, gels, foams, sprays, orenemas. These dosage forms can be manufactured using conventionalprocesses as described in Remington: The Science and Practice ofPharmacy, supra.

Rectal, urethral, and vaginal suppositories are solid bodies forinsertion into body orifices, which are solid at ordinary temperaturesbut melt or soften at body temperature to release the activeingredient(s) inside the orifices. Pharmaceutically acceptable carriersutilized in rectal and vaginal suppositories include bases or vehicles,such as stiffening agents, which produce a melting point in theproximity of body temperature, when formulated with the pharmaceuticalcompositions provided herein; and antioxidants as described herein,including bisulfite and sodium metabisulfite. Suitable vehicles include,but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin,carbowax (polyoxyethylene glycol), spermaceti, paraffin, white andyellow wax, and appropriate mixtures of mono-, di- and triglycerides offatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethylmethacrylate, and polyacrylic acid. Combinations of the various vehiclescan also be used. Rectal and vaginal suppositories may be prepared bycompressing or molding. The typical weight of a rectal and vaginalsuppository is about 2 to about 3 g.

The pharmaceutical compositions provided herein can be administeredophthalmically in the forms of solutions, suspensions, ointments,emulsions, gel-forming solutions, powders for solutions, gels, ocularinserts, and implants.

The pharmaceutical compositions provided herein can be administeredintranasally or by inhalation to the respiratory tract. Thepharmaceutical compositions can be provided in the form of an aerosol orsolution for delivery using a pressurized container, pump, spray,atomizer, such as an atomizer using electrohydrodynamics to produce afine mist, or nebulizer, alone or in combination with a suitablepropellant, such as 1,1,1,2-tetrafluoroethane or1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions canalso be provided as a dry powder for insufflation, alone or incombination with an inert carrier such as lactose or phospholipids; andnasal drops. For intranasal use, the powder can comprise a bioadhesiveagent, including chitosan or cyclodextrin.

Solutions or suspensions for use in a pressurized container, pump,spray, atomizer, or nebulizer can be formulated to contain ethanol,aqueous ethanol, or a suitable alternative agent for dispersing,solubilizing, or extending release of the active ingredient providedherein; a propellant as solvent; and/or a surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

The pharmaceutical compositions provided herein can be micronized to asize suitable for delivery by inhalation, such as about 50 micrometersor less, or about 10 micrometers or less. Particles of such sizes can beprepared using a comminuting method known to those skilled in the art,such as spiral jet milling, fluid bed jet milling, supercritical fluidprocessing to form nanoparticles, high pressure homogenization, or spraydrying.

Capsules, blisters, and cartridges for use in an inhaler or insufflatorcan be formulated to contain a powder mix of the pharmaceuticalcompositions provided herein; a suitable powder base, such as lactose orstarch; and a performance modifier, such as l-leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form of themonohydrate. Other suitable excipients or carriers include, but are notlimited to, dextran, glucose, maltose, sorbitol, xylitol, fructose,sucrose, and trehalose. The pharmaceutical compositions provided hereinfor inhaled/intranasal administration can further comprise a suitableflavor, such as menthol and levomenthol; and/or sweeteners, such assaccharin and saccharin sodium.

The pharmaceutical compositions provided herein for topicaladministration can be formulated to be immediate release or modifiedrelease, including delayed-, sustained-, pulsed-, controlled-, targeted,and programmed release.

D. Modified Release

The pharmaceutical compositions provided herein can be formulated as amodified release dosage form. As used herein, the term “modifiedrelease” refers to a dosage form in which the rate or place of releaseof the active ingredient(s) is different from that of an immediatedosage form when administered by the same route. Modified release dosageforms include, but are not limited to, delayed-, extended-, prolonged-,sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-,programmed-release, and gastric retention dosage forms. Thepharmaceutical compositions in modified release dosage forms can beprepared using a variety of modified release devices and methods knownto those skilled in the art, including, but not limited to, matrixcontrolled release devices, osmotic controlled release devices,multiparticulate controlled release devices, ion-exchange resins,enteric coatings, multilayered coatings, microspheres, liposomes, andcombinations thereof. The release rate of the active ingredient(s) canalso be modified by varying the particle sizes and polymorphorism of theactive ingredient(s).

Examples of modified release include, but are not limited to, thosedescribed in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543;5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474;5,922,356; 5,958,458; 5,972,891; 5,980,945; 5,993,855; 6,045,830;6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981;6,270,798; 6,375,987; 6,376,461; 6,419,961; 6,589,548; 6,613,358;6,623,756; 6,699,500; 6,793,936; 6,827,947; 6,902,742; 6,958,161;7,255,876; 7,416,738; 7,427,414; 7,485,322; Bussemer et al., Crit. Rev.Ther. Drug Carrier Syst. 2001, 18, 433-458; Modified-Release DrugDelivery Technology, 2nd ed.; Rathbone et al., Eds.; Marcel Dekker A G:2005; Maroni et al., Expert. Opin. Drug Deliv. 2005, 2, 855-871; Shi etal., Expert Opin. Drug Deliv. 2005, 2, 1039-1058; Polymers in DrugDelivery; Ijeoma et al., Eds.; CRC Press LLC: Boca Raton, Fla., 2006;Badawy et al., J. Pharm. Sci. 2007, 9, 948-959; Modified-Release DrugDelivery Technology, supra; Conway, Recent Pat. Drug Deliv. Formul.2008, 2, 1-8; Gazzaniga et al., Eur. J. Pharm. Biopharm. 2008, 68,11-18; Nagarwal et al., Curr. Drug Deliv. 2008, 5, 282-289; Gallardo etal., Pharm. Dev. Technol. 2008, 13, 413-423; Chrzanowski, AAPSPharmSciTech. 2008, 9, 635-638; Chrzanowski, AAPS PharmSciTech. 2008, 9,639-645; Kalantzi et al., Recent Pat. Drug Deliv. Formul. 2009, 3,49-63; Saigal et al., Recent Pat. Drug Deliv. Formul. 2009, 3, 64-70;and Roy et al., J. Control Release 2009, 134, 74-80.

1. Matrix Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated using a matrix controlled release deviceknown to those skilled in the art. See, Takada et al. in Encyclopedia ofControlled Drug Delivery; Mathiowitz Ed.; Wiley: 1999; Vol 2.

In certain embodiments, the pharmaceutical compositions provided hereinin a modified release dosage form is formulated using an erodible matrixdevice, which is water-swellable, erodible, or soluble polymers,including, but not limited to, synthetic polymers, and naturallyoccurring polymers and derivatives, such as polysaccharides andproteins.

Materials useful in forming an erodible matrix include, but are notlimited to, chitin, chitosan, dextran, and pullulan; gum agar, gumarabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gumghatti, guar gum, xanthan gum, and scleroglucan; starches, such asdextrin and maltodextrin; hydrophilic colloids, such as pectin;phosphatides, such as lecithin; alginates; propylene glycol alginate;gelatin; collagen; cellulosics, such as ethyl cellulose (EC),methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), celluloseacetate (CA), cellulose propionate (CP), cellulose butyrate (CB),cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetatetrimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC);polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerolfatty acid esters; polyacrylamide; polyacrylic acid; copolymers ofethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc.,Piscataway, N.J.); poly(2-hydroxyethyl-methacrylate); polylactides;copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lacticacid-glycolic acid copolymers; poly-D-(−)-3-hydroxybutyric acid; andother acrylic acid derivatives, such as homopolymers and copolymers ofbutylmethacrylate, methyl methacrylate, ethyl methacrylate,ethylacrylate, (2-dimethylaminoethyl)methacrylate, and(trimethylaminoethyl)methacrylate chloride.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated with a non-erodible matrix device. The activeingredient(s) is dissolved or dispersed in an inert matrix and isreleased primarily by diffusion through the inert matrix onceadministered. Materials suitable for use as a non-erodible matrix deviceinclude, but are not limited to, insoluble plastics, such aspolyethylene, polypropylene, polyisoprene, polyisobutylene,polybutadiene, polymethylmethacrylate, polybutylmethacrylate,chlorinated polyethylene, polyvinylchloride, methyl acrylate-methylmethacrylate copolymers, ethylene-vinyl acetate copolymers,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethyleneand propylene, ionomer polyethylene terephthalate, butyl rubbers,epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer,ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticizednylon, plasticized polyethylene terephthalate, natural rubber, siliconerubbers, polydimethylsiloxanes, and silicone carbonate copolymers;hydrophilic polymers, such as ethyl cellulose, cellulose acetate,crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate;and fatty compounds, such as carnauba wax, microcrystalline wax, andtriglycerides.

In a matrix controlled release system, the desired release kinetics canbe controlled, for example, via the polymer type employed, the polymerviscosity, the particle sizes of the polymer and/or the activeingredient(s), the ratio of the active ingredient(s) versus the polymer,and other excipients or carriers in the compositions.

The pharmaceutical compositions provided herein in a modified releasedosage form can be prepared by methods known to those skilled in theart, including direct compression, dry or wet granulation followed bycompression, and melt-granulation followed by compression.

2. Osmotic Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated using an osmotic controlled releasedevice, including, but not limited to, one-chamber system, two-chambersystem, asymmetric membrane technology (AMT), and extruding core system(ECS). In general, such devices have at least two components: (a) a corewhich contains an active ingredient; and (b) a semipermeable membranewith at least one delivery port, which encapsulates the core. Thesemipermeable membrane controls the influx of water to the core from anaqueous environment of use so as to cause drug release by extrusionthrough the delivery port(s).

In addition to the active ingredient(s), the core of the osmotic deviceoptionally includes an osmotic agent, which creates a driving force fortransport of water from the environment of use into the core of thedevice. One class of osmotic agents is water-swellable hydrophilicpolymers, which are also referred to as “osmopolymers” and “hydrogels.”Suitable water-swellable hydrophilic polymers as osmotic agents include,but are not limited to, hydrophilic vinyl and acrylic polymers,polysaccharides such as calcium alginate, polyethylene oxide (PEO),polyethylene glycol (PEG), polypropylene glycol (PPG),poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic)acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol(PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomerssuch as methyl methacrylate and vinyl acetate, hydrophilic polyurethanescontaining large PEO blocks, sodium croscarmellose, carrageenan,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) andcarboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin,xanthan gum, and sodium starch glycolate.

The other class of osmotic agents is osmogens, which are capable ofimbibing water to affect an osmotic pressure gradient across the barrierof the surrounding coating. Suitable osmogens include, but are notlimited to, inorganic salts, such as magnesium sulfate, magnesiumchloride, calcium chloride, sodium chloride, lithium chloride, potassiumsulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithiumsulfate, potassium chloride, and sodium sulfate; sugars, such asdextrose, fructose, glucose, inositol, lactose, maltose, mannitol,raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids,such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleicacid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamicacid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea;and mixtures thereof.

Osmotic agents of different dissolution rates can be employed toinfluence how rapidly the active ingredient(s) is initially deliveredfrom the dosage form. For example, amorphous sugars, such as MANNOGEM™EZ (SPI Pharma, Lewes, Del.) can be used to provide faster deliveryduring the first couple of hours to promptly produce the desiredtherapeutic effect, and gradually and continually release of theremaining amount to maintain the desired level of therapeutic orprophylactic effect over an extended period of time. In this case, theactive ingredient(s) is released at such a rate to replace the amount ofthe active ingredient metabolized and excreted.

The core can also include a wide variety of other excipients andcarriers as described herein to enhance the performance of the dosageform or to promote stability or processing.

Materials useful in forming the semipermeable membrane include variousgrades of acrylics, vinyls, ethers, polyamides, polyesters, andcellulosic derivatives that are water-permeable and water-insoluble atphysiologically relevant pHs, or are susceptible to being renderedwater-insoluble by chemical alteration, such as crosslinking Examples ofsuitable polymers useful in forming the coating, include plasticized,unplasticized, and reinforced cellulose acetate (CA), cellulosediacetate, cellulose triacetate, CA propionate, cellulose nitrate,cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methylcarbamate, CA succinate, cellulose acetate trimellitate (CAT), CAdimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyloxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta glucan acetate, betaglucan triacetate, acetaldehyde dimethyl acetate, triacetate of locustbean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPGcopolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT,poly(acrylic) acids and esters and poly-(methacrylic) acids and estersand copolymers thereof, starch, dextran, dextrin, chitosan, collagen,gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones,polystyrenes, polyvinyl halides, polyvinyl esters and ethers, naturalwaxes, and synthetic waxes.

Semipermeable membrane can also be a hydrophobic microporous membrane,wherein the pores are substantially filled with a gas and are not wettedby the aqueous medium but are permeable to water vapor, as disclosed inU.S. Pat. No. 5,798,119. Such hydrophobic but water-vapor permeablemembrane are typically composed of hydrophobic polymers such aspolyalkenes, polyethylene, polypropylene, polytetrafluoroethylene,polyacrylic acid derivatives, polyethers, polysulfones,polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidenefluoride, polyvinyl esters and ethers, natural waxes, and syntheticwaxes.

The delivery port(s) on the semipermeable membrane can be formedpost-coating by mechanical or laser drilling. Delivery port(s) can alsobe formed in situ by erosion of a plug of water-soluble material or byrupture of a thinner portion of the membrane over an indentation in thecore. In addition, delivery ports can be formed during coating process,as in the case of asymmetric membrane coatings of the type disclosed inU.S. Pat. Nos. 5,612,059 and 5,698,220.

The total amount of the active ingredient(s) released and the releaserate can substantially by modulated via the thickness and porosity ofthe semipermeable membrane, the composition of the core, and the number,size, and position of the delivery ports.

The pharmaceutical compositions in an osmotic controlled-release dosageform can further comprise additional conventional excipients or carriersas described herein to promote performance or processing of theformulation.

The osmotic controlled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art.See, Remington: The Science and Practice of Pharmacy, supra; Santus andBaker, J. Controlled Release 1995, 35, 1-21; Verma et al., DrugDevelopment and Industrial Pharmacy 2000, 26, 695-708; and Verma et al.,J. Controlled Release 2002, 79, 7-27.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as AMT controlled-release dosage form, which comprises anasymmetric osmotic membrane that coats a core comprising the activeingredient(s) and other pharmaceutically acceptable excipients orcarriers. See, U.S. Pat. No. 5,612,059 and International Pat. Appl.Publ. No. WO 2002/17918. The AMT controlled-release dosage forms can beprepared according to conventional methods and techniques known to thoseskilled in the art, including direct compression, dry granulation, wetgranulation, and a dip-coating method.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as ESC controlled-release dosage form, which comprises anosmotic membrane that coats a core comprising the active ingredient(s),a hydroxylethyl cellulose, and other pharmaceutically acceptableexcipients or carriers.

3. Multiparticulate Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated as a multiparticulate controlled releasedevice, which comprises a multiplicity of particles, granules, orpellets, ranging from about 10 μm to about 3 mm, about 50 μm to about2.5 mm, or from about 100 μm to about 1 mm in diameter. Suchmultiparticulates can be made by the processes known to those skilled inthe art, including wet- and dry-granulation, extrusion/spheronization,roller-compaction, melt-congealing, and by spray-coating seed cores.See, for example, Multiparticulate Oral Drug Delivery; Ghebre-SellassieEd.; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology;Ghebre-Sellassie Ed.; Marcel Dekker: 1989.

Other excipients or carriers as described herein can be blended with thepharmaceutical compositions to aid in processing and forming themultiparticulates. The resulting particles can themselves constitute themultiparticulate device or can be coated by various film-formingmaterials, such as enteric polymers, water-swellable, and water-solublepolymers. The multiparticulates can be further processed as a capsule ora tablet.

4. Targeted Delivery

The pharmaceutical compositions provided herein can also be formulatedto be targeted to a particular tissue, receptor, or other area of thebody of the subject to be treated, including liposome-, resealederythrocyte-, and antibody-based delivery systems. Examples include, butare not limited to, those disclosed in U.S. Pat. Nos. 5,709,874;5,759,542; 5,840,674; 5,900,252; 5,972,366; 5,985,307; 6,004,534;6,039,975; 6,048,736; 6,060,082; 6,071,495; 6,120,751; 6,131,570;6,139,865; 6,253,872; 6,271,359; 6,274,552; 6,316,652; and 7,169,410.

Methods of Use

In one embodiment, provided herein is a method for treating, preventing,or ameliorating one or more symptoms of an ERBB-mediated condition,disorder, or disease in a subject, comprising administering to thesubject a compound disclosed herein, e.g., a compound of Formula I, or asingle enantiomer, a racemic mixture, a mixture of diastereomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof.

In certain embodiments, the ERBB is a wild-type ERBB. In certainembodiments, the ERBB is an ERBB variant.

In certain embodiments, the ERBB is an EGFR. In certain embodiments, theERBB is a wild-type EGFR. In certain embodiments, the ERBB is an EGFRvariant. In certain embodiments, the EGFR variant contains a deletion,insertion, or substitution. In certain embodiments, the EGFR variantcontains one or more deletions, insertions, or substitutions at theamino acid positions of 689, 700, 709, 715, 719, 720, 746-759, 761-765,767-775, 783, 784, 790, 796, 826, 839, 846, 858, 861, and 863. Incertain embodiments, the EGFR variant contains one, two, or moredeletions, insertions, and/or substitutions, each independently selectedfrom V689M, N700D, E709K, E709Q, E709V, E709A, E709G, I715S, G719C,G719S, G719A, S720P, ΔE746-A750, ΔE746-T751, ΔE746-A750 (ins RP),ΔE746-T751 (ins A/I), ΔE746-T751 (ins VA), ΔE746-S752 (ins A/V), L747S,ΔL747-E749 (A750P), ΔL747-A750 (ins P), ΔL747-T751, ΔL747-T751 (insP/S), ΔL747-S752, ΔL747-752 (E746V), ΔL747-752 (P753S), ΔL747-S752 (insQ), ΔL747-P753, ΔL747-P753 (ins S), ΔS752-1759, D761Y, ΔD761-E762 (insEAFQ), ΔA763-Y764 (ins FQEA), V765A, ΔM766-A767 (ins AI), ΔA767-S768(ins TLA), ΔA767-S768 (ins SVA), S768I, ΔS768-D770 (dup SVD), V769L,ΔV769-D770 (ins ASV), ΔD770-N771 (ins NPG), ΔD770-N771 (ins SVQ),ΔD770-N771 (ins SVD), ΔD770-N771 (ins G), ΔD770-P772 (ins ASV), N771T,ΔP772-H773 (ins PR), ΔP772-H773 (ins YNP), ΔH773-V774 (ins NPH),ΔH773-V774 (ins NP), ΔH773-V774 (ins H), ΔH773-V774 (ins PH), ΔH773-V774(ins GNPH), ΔV774-C775 (ins HV), H775Y, P782R, T783A, T784A, T790M,G796A, N826S, A839T, K846R, L858R, L861Q, and G863D, provided that thereis only one deletion and/or insertion, or substitution at a given aminoacid position in the EGFR variant. In certain embodiments, the EGFRvariant contains one, two, or more deletions, insertions, and/orsubstitutions, each independently selected from G719C, G719S. G719A,ΔE746-A750, ΔE746-T751, ΔE746-A750 (ins RP), T790M, and L858R. Incertain embodiments, the EGFR variant contains T790M and/or L858R. Incertain embodiments, the EGFR variant contains one, two, or moredeletions, insertions, and/or substitutions, each independently selectedfrom ΔD761-E762 (ins EAFQ), ΔS768-D770 (dup SVD), ΔV769-D770 (ins ASV),ΔD770-N771 (ins SVQ), ΔP772-H773 (ins PR), ΔH773-V774 (ins NPH),ΔH773-V774 (ins H), ΔH773-V774 (ins PH), and ΔH773-V774 (ins GNPH). Incertain embodiments, the EGFR variant contains a deletion, insertion, orsubstitution in exon 19. In certain embodiments, the EGFR variantcontains a deletion, insertion, or substitution in exon 20.

In certain embodiments, the ERBB is a HER2. In certain embodiments, theERBB is a wild-type HER2. In certain embodiments, the ERBB is a HER2variant. In certain embodiments, the HER2 variant contains a deletion,insertion, or substitution. In certain embodiments, the HER2 variantcontains one or more deletions, insertions, or substitutions at theamino acid positions of 309, 310, 630, 717, 719, 726, 733, 755-759, 767,769, 775-778, 780, 781, 783, 785, 798, 803, 812, 821, 835, 839, 842,896, and 915. In certain embodiments, the HER2 variant contains one,two, or more deletions, insertions, and/or substitutions, eachindependently selected from G309A, G309E, S310F, C630Y, E717K, E719G,E719K, L726F, T7331, L755S, L755W, ΔL755-T759, I767M, D769H, D769Y,ΔA775-G776 (ins YVMA), G776VC, G776LC, ΔV777-G778 (ins CG), V777L,P780L, ΔP780-Y781 (ins GSP), S783P, L785F, T798I, Y803N, E812K, D821N,Y835F, V839G, V842I, R896C, and L915M, provided that there is only onedeletion and/or insertion, or substitution at a given amino acidposition in the HER2 variant. In certain embodiments, the HER2 variantcontains one, two, or more deletions, insertions, and/or substitutions,each independently selected from G309A, L755S, ΔL755-T759, ΔA775-G776(ins YVMA), V777L, ΔP780-Y781 (ins GSP), V842I, and R896C.

In certain embodiments, the ERBB is a HER3. In certain embodiments, theERBB is a wild-type HER3. In certain embodiments, the ERBB is a HER3variant. In certain embodiments, the HER3 variant contains a deletion,insertion, or substitution.

In certain embodiments, the ERBB is a HER4. In certain embodiments, theERBB is a wild-type HER4. In certain embodiments, the ERBB is a HER4variant. In certain embodiments, the HER4 variant contains a deletion,insertion, or substitution.

In certain embodiments, the ERBB is a dimer. In certain embodiments, theERBB is a homodimer. In certain embodiments, the ERBB is a heterodimer.In certain embodiments, the ERBB is a heterodimer of EGFR, HER2, HER3,HER4, and variants thereof.

In certain embodiments, the compound provided herein is a selectiveinhibitor of a mutant ERBB. In certain embodiments, the compoundprovided herein has a selectivity against a mutant ERBB over a wild-typeERBB ranging from about 2 fold, about 4 fold, about 8 fold, about 20fold, about 50 fold, about 100 fold, about 200 fold, about 500 fold, orabout 1000 fold.

In certain embodiments, the compound provided herein is a selectiveinhibitor of a mutant EGFR. In certain embodiments, the compoundprovided herein has a selectivity against a mutant EGFR over a wild-typeEGFR ranging from about 2 fold, about 4 fold, about 8 fold, about 20fold, about 50 fold, about 100 fold, about 200 fold, about 500 fold, orabout 1000 fold.

In certain embodiments, the compound provided herein is a selectiveinhibitor of a mutant HER2. In certain embodiments, the compoundprovided herein has a selectivity against a mutant HER2 over a wild-typeHER2 ranging from about 2 fold, about 4 fold, about 8 fold, about 20fold, about 50 fold, about 100 fold, about 200 fold, about 500 fold, orabout 1000 fold.

In certain embodiments, the compound provided herein is a selectiveinhibitor of a mutant HER3. In certain embodiments, the compoundprovided herein has a selectivity against a mutant HER3 over a wild-typeHER3 ranging from about 2 fold, about 4 fold, about 8 fold, about 20fold, about 50 fold, about 100 fold, about 200 fold, about 500 fold, orabout 1000 fold.

In certain embodiments, the compound provided herein is a selectiveinhibitor of a mutant HER4. In certain embodiments, the compoundprovided herein has a selectivity against a mutant HER4 over a wild-typeHER4 ranging from about 2 fold, about 4 fold, about 8 fold, about 20fold, about 50 fold, about 100 fold, about 200 fold, about 500 fold, orabout 1000 fold.

In another embodiments, provided herein is a method for treating,preventing, or ameliorating one or more symptoms of a proliferativedisease in a subject, comprising administering to the subject atherapeutically effective amount of a compound disclosed herein, e.g., acompound of Formula I, or an enantiomer, a mixture of enantiomers, amixture of two or more diastereomers, or an isotopic variant thereof; ora pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof.

In certain embodiments, the subject is a mammal. In certain embodiments,the subject is a human. In certain embodiments, the subject is a primateother than a human, a farm animal such as cattle, a sport animal, or apet such as a horse, dog, or cat.

In certain embodiments, the ERBB-mediated condition, disorder, ordisease is a proliferative disease. In certain embodiments, theERBB-mediated condition, disorder, or disease is cancer. In certainembodiments, the ERBB-mediated condition, disorder, or disease is adrug-resistant cancer. In certain embodiments, the ERBB-mediatedcondition, disorder, or disease is multidrug-resistant cancer. Incertain embodiments, the ERBB-mediated condition, disorder, or diseaseis relapsed multidrug-resistant cancer. In certain embodiments, theERBB-mediated condition, disorder, or disease is an inflammatorydisease. In certain embodiments, the ERBB-mediated condition, disorder,or disease is an immune disorder.

In certain embodiments, the proliferative disease is cancer. In certainembodiments, the cancer is relapsed cancer. In certain embodiments, thecancer is drug-resistant cancer. In certain embodiments, the cancer isrelapsed drug-resistant cancer. In certain embodiments, the cancer ismultidrug-resistant cancer. In certain embodiments, the cancer isrelapsed multidrug-resistant cancer.

In certain embodiments, the cancer is ERBB inhibitor-resistant cancer.In certain embodiments, the cancer is reversible ERBBinhibitor-resistant cancer. In certain embodiments, the cancer isirreversible ERBB inhibitor-resistant cancer. In certain embodiments,the cancer is relapsed ERBB inhibitor-resistant cancer. In certainembodiments, the cancer is relapsed reversible ERBB inhibitor-resistantcancer. In certain embodiments, the cancer is relapsed irreversible ERBBinhibitor-resistant cancer. In certain embodiments, the cancer isresistant to afatinib, canertinib, dacomitinib, erlotinib, gefitinib,icotinib, lapatinib, neratinib, pelitinib, varlitinib, or a combinationthereof.

In certain embodiments, the cancer is EGFR inhibitor-resistant cancer.In certain embodiments, the cancer is reversible EGFRinhibitor-resistant cancer. In certain embodiments, the cancer isirreversible EGFR inhibitor-resistant cancer. In certain embodiments,the cancer is relapsed EGFR inhibitor-resistant cancer. In certainembodiments, the cancer is relapsed reversible EGFR inhibitor-resistantcancer. In certain embodiments, the cancer is relapsed irreversible EGFRinhibitor-resistant cancer.

In certain embodiments, the cancer is HER2 inhibitor-resistant cancer.In certain embodiments, the cancer is reversible HER2inhibitor-resistant cancer. In certain embodiments, the cancer isirreversible HER2 inhibitor-resistant cancer. In certain embodiments,the cancer is relapsed HER2 inhibitor-resistant cancer. In certainembodiments, the cancer is relapsed reversible HER2 inhibitor-resistantcancer. In certain embodiments, the cancer is relapsed irreversible HER2inhibitor-resistant cancer.

In certain embodiments, the cancer is HER3 inhibitor-resistant cancer.In certain embodiments, the cancer is reversible HER3inhibitor-resistant cancer. In certain embodiments, the cancer isirreversible HER3 inhibitor-resistant cancer. In certain embodiments,the cancer is relapsed HER3 inhibitor-resistant cancer. In certainembodiments, the cancer is relapsed reversible HER3 inhibitor-resistantcancer. In certain embodiments, the cancer is relapsed irreversible HER3inhibitor-resistant cancer.

In certain embodiments, the cancer is HER4 inhibitor-resistant cancer.In certain embodiments, the cancer is reversible HER4inhibitor-resistant cancer. In certain embodiments, the cancer isirreversible HER4 inhibitor-resistant cancer. In certain embodiments,the cancer is relapsed HER4 inhibitor-resistant cancer. In certainembodiments, the cancer is relapsed reversible HER4 inhibitor-resistantcancer. In certain embodiments, the cancer is relapsed irreversible HER4inhibitor-resistant cancer.

In certain embodiments, the proliferative disease is an inflammatorydisease. In certain embodiments, the proliferative disease is an immunedisorder.

The conditions, disorders, or diseases treatable with a compoundprovided herein include, but are not limited to, (1) inflammatory orallergic diseases, including systemic anaphylaxis and hypersensitivitydisorders, atopic dermatitis, urticaria, drug allergies, insect stingallergies, food allergies (including celiac disease and the like), andmastocytosis; (2) inflammatory bowel diseases, including Crohn'sdisease, ulcerative colitis, ileitis, and enteritis; (3) vasculitis, andBehcet's syndrome; (4) psoriasis and inflammatory dermatoses, includingdermatitis, eczema, atopic dermatitis, allergic contact dermatitis,urticaria, viral cutaneous pathologies including those derived fromhuman papillomavirus, HIV or RLV infection, bacterial, flugal, and otherparasital cutaneous pathologies, and cutaneous lupus erythematosus; (5)asthma and respiratory allergic diseases, including allergic asthma,exercise induced asthma, allergic rhinitis, otitis media, allergicconjunctivitis, hypersensitivity lung diseases, and chronic obstructivepulmonary disease; (6) autoimmune diseases, including arthritis(including rheumatoid and psoriatic), systemic lupus erythematosus, typeI diabetes, myasthenia gravis, multiple sclerosis, Graves' disease, andglomerulonephritis; (7) graft rejection (including allograft rejectionand graft-v-host disease), e.g., skin graft rejection, solid organtransplant rejection, bone marrow transplant rejection; (8) fever; (9)cardiovascular disorders, including acute heart failure, hypotension,hypertension, angina pectoris, myocardial infarction, cardiomyopathy,congestive heart failure, atherosclerosis, coronary artery disease,restenosis, and vascular stenosis; (10) cerebrovascular disorders,including traumatic brain injury, stroke, ischemic reperfusion injuryand aneurysm; (11) cancers of the breast, skin, prostate, cervix,uterus, ovary, testes, bladder, lung, liver, larynx, oral cavity, colonand gastrointestinal tract (e.g., esophagus, stomach, pancreas), brain,thyroid, blood, and lymphatic system; (12) fibrosis, connective tissuedisease, and sarcoidosis, (13) genital and reproductive conditions,including erectile dysfunction; (14) gastrointestinal disorders,including gastritis, ulcers, nausea, pancreatitis, and vomiting; (15)neurologic disorders, including Alzheimer's disease; (16) sleepdisorders, including insomnia, narcolepsy, sleep apnea syndrome, andPickwick Syndrome; (17) pain; (18) renal disorders; (19) oculardisorders, including glaucoma; and (20) infectious diseases, includingHIV.

In certain embodiments, the cancer treatable with a compound providedherein includes, but is not limited to, (1) leukemias, including, butnot limited to, acute leukemia, acute lymphocytic leukemia, acutemyelocytic leukemias such as myeloblastic, promyelocytic,myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplasticsyndrome or a symptom thereof (such as anemia, thrombocytopenia,neutropenia, bicytopenia or pancytopenia), refractory anemia (RA), RAwith ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB intransformation (RAEB-T), preleukemia, and chronic myelomonocyticleukemia (CMML), (2) chronic leukemias, including, but not limited to,chronic myelocytic (granulocytic) leukemia, chronic lymphocyticleukemia, and hairy cell leukemia; (3) polycythemia vera; (4) lymphomas,including, but not limited to, Hodgkin's disease and non-Hodgkin'sdisease; (5) multiple myelomas, including, but not limited to,smoldering multiple myeloma, nonsecretory myeloma, osteoscleroticmyeloma, plasma cell leukemia, solitary plasmacytoma, and extramedullaryplasmacytoma; (6) Waldenstrom's macroglobulinemia; (7) monoclonalgammopathy of undetermined significance; (8) benign monoclonalgammopathy; (9) heavy chain disease; (10) bone and connective tissuesarcomas, including, but not limited to, bone sarcoma, osteosarcoma,chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor,fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissuesarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi'ssarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastaticcancers, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma; (11)brain tumors, including, but not limited to, glioma, astrocytoma, brainstem glioma, ependymoma, oligodendroglioma, nonglial tumor, acousticneurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma,pineoblastoma, and primary brain lymphoma; (12) breast cancer,including, but not limited to, adenocarcinoma, lobular (small cell)carcinoma, intraductal carcinoma, medullary breast cancer, mucinousbreast cancer, tubular breast cancer, papillary breast cancer, primarycancers, Paget's disease, and inflammatory breast cancer; (13) adrenalcancer, including, but not limited to, pheochromocytom andadrenocortical carcinoma; (14) thyroid cancer, including, but notlimited to, papillary or follicular thyroid cancer, medullary thyroidcancer, and anaplastic thyroid cancer; (15) pancreatic cancer,including, but not limited to, insulinoma, gastrinoma, glucagonoma,vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor;(16) pituitary cancer, including, but limited to, Cushing's disease,prolactin-secreting tumor, acromegaly, and diabetes insipius; (17) eyecancer, including, but not limited, to ocular melanoma such as irismelanoma, choroidal melanoma, and cilliary body melanoma, andretinoblastoma; (18) vaginal cancer, including, but not limited to,squamous cell carcinoma, adenocarcinoma, and melanoma; (19) vulvarcancer, including, but not limited to, squamous cell carcinoma,melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget'sdisease; (20) cervical cancers, including, but not limited to, squamouscell carcinoma, and adenocarcinoma; (21) uterine cancer, including, butnot limited to, endometrial carcinoma and uterine sarcoma; (22) ovariancancer, including, but not limited to, ovarian epithelial carcinoma,borderline tumor, germ cell tumor, and stromal tumor; (23) esophagealcancer, including, but not limited to, squamous cancer, adenocarcinoma,adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamouscarcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oatcell (small cell) carcinoma; (24) stomach cancer, including, but notlimited to, adenocarcinoma, fungating (polypoid), ulcerating,superficial spreading, diffusely spreading, malignant lymphoma,liposarcoma, fibrosarcoma, and carcinosarcoma; (25) colon cancer; (26)rectal cancer; (27) liver cancer, including, but not limited to,hepatocellular carcinoma and hepatoblastoma; (28) gallbladder cancer,including, but not limited to, adenocarcinoma; (29) cholangiocarcinomas,including, but not limited to, pappillary, nodular, and diffuse; (30)lung cancer, including, but not limited to, non-small cell lung cancer,squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma,large-cell carcinoma, and small-cell lung cancer; (31) testicularcancer, including, but not limited to, germinal tumor, seminoma,anaplastic, classic (typical), spermatocytic, nonseminoma, embryonalcarcinoma, teratoma carcinoma, and choriocarcinoma (yolk-sac tumor);(32) prostate cancer, including, but not limited to, adenocarcinoma,leiomyosarcoma, and rhabdomyosarcoma; (33) penal cancer; (34) oralcancer, including, but not limited to, squamous cell carcinoma; (35)basal cancer; (36) salivary gland cancer, including, but not limited to,adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma;(37) pharynx cancer, including, but not limited to, squamous cell cancerand verrucous; (38) skin cancer, including, but not limited to, basalcell carcinoma, squamous cell carcinoma and melanoma, superficialspreading melanoma, nodular melanoma, lentigo malignant melanoma, andacral lentiginous melanoma; (39) kidney cancer, including, but notlimited to, renal cell cancer, adenocarcinoma, hypernephroma,fibrosarcoma, and transitional cell cancer (renal pelvis and/or uterer);(40) Wilms' tumor; (41) bladder cancer, including, but not limited to,transitional cell carcinoma, squamous cell cancer, adenocarcinoma, andcarcinosarcoma; and other cancer, including, not limited to,myxosarcoma, osteogenic sarcoma, endotheliosarcoma,lymphangio-endotheliosarcoma, mesothelioma, synovioma, hemangioblastoma,epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweatgland carcinoma, sebaceous gland carcinoma, papillary carcinoma, andpapillary adenocarcinomas (See Fishman et al., 1985, Medicine, 2d Ed.,J. B. Lippincott Co., Philadelphia and Murphy et al., 1997, InformedDecisions: The Complete Book of Cancer Diagnosis, Treatment, andRecovery, Viking Penguin, Penguin Books U.S.A., Inc., United States ofAmerica).

In certain embodiments, the proliferative disease is bladder cancer,brain tumor, breast cancer, cancer of the mouth and throat, colorectalcancer, lung cancer, or pancreatic cancer, prostate cancer, stomachcancer, or uterine cancer.

In certain embodiments, the proliferative disease is lung cancer. Incertain embodiments, the proliferative disease is drug-resistant lungcancer. In certain embodiments, the proliferative disease ismultidrug-resistant lung cancer. In certain embodiments, theproliferative disease is relapsed lung cancer. In certain embodiments,the proliferative disease is relapsed drug-resistant lung cancer. Incertain embodiments, the proliferative disease is relapsedmultidrug-resistant lung cancer. In certain embodiments, theproliferative disease is non-small cell lung cancer. In certainembodiments, the proliferative disease is drug resistant non-small celllung cancer. In certain embodiments, the proliferative disease ismultidrug resistant non-small cell lung cancer. In certain embodiments,the proliferative disease is relapsed non-small cell lung cancer. Incertain embodiments, the proliferative disease is relapsed drugresistant non-small cell lung cancer. In certain embodiments, theproliferative disease is relapsed multidrug resistant non-small celllung cancer.

Depending on the disorder, disease, or condition to be treated, and thesubject's condition, the compounds or pharmaceutical compositionsprovided herein can be administered by oral, parenteral (e.g.,intramuscular, intraperitoneal, intravenous, ICV, intracistemalinjection or infusion, subcutaneous injection, or implant), inhalation,nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal orlocal) routes of administration and can be formulated, alone ortogether, in suitable dosage unit with pharmaceutically acceptableexcipients, carriers, adjuvants, and vehicles appropriate for each routeof administration. Also provided is administration of the compounds orpharmaceutical compositions provided herein in a depot formulation, inwhich the active ingredient is released over a predefined time period.

In the treatment, prevention, or amelioration of one or more symptoms ofthe disorders, diseases, or conditions described herein, an appropriatedosage level generally is ranging from about 0.001 to 100 mg per kgsubject body weight per day (mg/kg per day), from about 0.01 to about 75mg/kg per day, from about 0.1 to about 50 mg/kg per day, from about 0.5to about 25 mg/kg per day, or from about 1 to about 20 mg/kg per day,which can be administered in single or multiple doses. Within thisrange, the dosage can be ranging from about 0.005 to about 0.05, fromabout 0.05 to about 0.5, from about 0.5 to about 5.0, from about 1 toabout 15, from about 1 to about 20, or from about 1 to about 50 mg/kgper day.

For oral administration, the pharmaceutical compositions provided hereincan be formulated in the form of tablets containing from about 1.0 toabout 1,000 mg of the active ingredient, in one embodiment, about 1,about 5, about 10, about 15, about 20, about 25, about 50, about 75,about 100, about 150, about 200, about 250, about 300, about 400, about500, about 600, about 750, about 800, about 900, and about 1,000 mg ofthe active ingredient for the symptomatic adjustment of the dosage tothe patient to be treated. The pharmaceutical compositions can beadministered on a regimen of 1 to 4 times per day, including once,twice, three times, and four times per day.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient can be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

In one embodiment, provided herein is a method of inhibiting the growthof a cell, comprising contacting the cell with a compound providedherein, e.g., a compound of Formula I, or a single enantiomer, a racemicmixture, a mixture of diastereomers, or an isotopic variant thereof; ora pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, provided herein is a method of inhibiting thegrowth of a cell in a subject, comprising administering to the subject acompound disclosed herein, e.g., a compound of Formula I, or a singleenantiomer, a racemic mixture, a mixture of diastereomers, or anisotopic variant thereof or a pharmaceutically acceptable salt, solvate,or prodrug thereof.

In certain embodiments, the cell is a cancer cell. In certainembodiments, the cell contains an ERBB variant.

In one embodiment, provided herein is a method for modulating theactivity of a tyrosine kinase, in one embodiment, an ERBB kinase,comprising contacting the ERBB kinase with a compound disclosed herein,e.g., a compound of Formula I, or a single enantiomer, a racemicmixture, a mixture of diastereomers, or an isotopic variant thereof or apharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, provided herein is a method for modulating theactivity of a tyrosine kinase, in one embodiment, an ERBB kinase, in asubject, comprising administering to the subject a compound disclosedherein, e.g., a compound of Formula I, or a single enantiomer, a racemicmixture, a mixture of diastereomers, or an isotopic variant thereof or apharmaceutically acceptable salt, solvate, or prodrug thereof.

In certain embodiments, the ERBB is a wild-type type ERBB. In certainembodiments, the ERBB is an ERBB variant. In certain embodiments, theERBB is an EGFR. In certain embodiments, the ERBB is a wild-type EGFR.In certain embodiments, the ERBB is an EGFR variant. In certainembodiments, the ERBB is a HER2. In certain embodiments, the ERBB is awild-type HER2. In certain embodiments, the ERBB is a HER2 variant. Incertain embodiments, the ERBB is a HER3. In certain embodiments, theERBB is a wild-type HER3. In certain embodiments, the ERBB is a HER3variant. In certain embodiments, the ERBB is a HER4. In certainembodiments, the ERBB is a wild-type HER4. In certain embodiments, theERBB is a HER4 variant.

The compound provided herein, e.g., a compound of Formula I, or anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof can also becombined or used in combination with other agents or therapies useful inthe treatment, prevention, or amelioration of one or more symptoms ofthe conditions, disorders, or diseases for which the compounds providedherein are useful.

Suitable other therapeutic agents can also include, but are not limitedto, (1) alpha-adrenergic agents; (2) antiarrhythmic agents; (3)anti-atherosclerotic agents, such as ACAT inhibitors; (4) antibiotics,such as anthracyclines, bleomycins, mitomycin, dactinomycin, andplicamycin; (5) anticancer agents and cytotoxic agents, e.g., alkylatingagents, such as nitrogen mustards, alkyl sulfonates, nitrosoureas,ethylenimines, and triazenes; (6) anticoagulants, such as acenocoumarol,argatroban, bivalirudin, lepirudin, fondaparinux, heparin, phenindione,warfarin, and ximelagatran; (7) anti-diabetic agents, such as biguanides(e.g., metformin), glucosidase inhibitors (e.g., acarbose), insulins,meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride,glyburide, and glipizide), thiozolidinediones (e.g., troglitazone,rosiglitazone, and pioglitazone), and PPAR-gamma agonists; (8)antifungal agents, such as amorolfine, amphotericin B, anidulafungin,bifonazole, butenafine, butoconazole, caspofungin, ciclopirox,clotrimazole, econazole, fenticonazole, filipin, fluconazole,isoconazole, itraconazole, ketoconazole, micafungin, miconazole,naftifine, natamycin, nystatin, oxyconazole, ravuconazole, posaconazole,rimocidin, sertaconazole, sulconazole, terbinafine, terconazole,tioconazole, and voriconazole; (9) antiinflammatories, e.g.,non-steroidal anti-inflammatory agents, such as aceclofenac, acemetacin,amoxiprin, aspirin, azapropazone, benorilate, bromfenac, carprofen,celecoxib, choline magnesium salicylate, diclofenac, diflunisal,etodolac, etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen,ibuprofen, indometacin, ketoprofen, ketorolac, lornoxicam, loxoprofen,lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam, metamizole,methyl salicylate, magnesium salicylate, nabumetone, naproxen,nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, piroxicam,salicyl salicylate, sulindac, sulfinpyrazone, suprofen, tenoxicam,tiaprofenic acid, and tolmetin; (10) antimetabolites, such as folateantagonists, purine analogues, and pyrimidine analogues; (11)anti-platelet agents, such as GPIIb/IIIa blockers (e.g., abciximab,eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g., clopidogrel,ticlopidine and CS-747), cilostazol, dipyridamole, and aspirin; (12)antiproliferatives, such as methotrexate, FK506 (tacrolimus), andmycophenolate mofetil; (13) anti-TNF antibodies or soluble TNF receptor,such as etanercept, rapamycin, and leflunimide; (14) aP2 inhibitors;(15) beta-adrenergic agents, such as carvedilol and metoprolol; (16)bile acid sequestrants, such as questran; (17) calcium channel blockers,such as amlodipine besylate; (18) chemotherapeutic agents; (19)cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib and rofecoxib;(20) cyclosporins; (21) cytotoxic drugs, such as azathioprine andcyclophosphamide; (22) diuretics, such as chlorothiazide,hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzothiazide, ethacrynic acid, ticrynafen,chlorthalidone, furosenide, muzolimine, bumetanide, triamterene,amiloride, and spironolactone; (23) endothelin converting enzyme (ECE)inhibitors, such as phosphoramidon; (24) enzymes, such asL-asparaginase; (25) Factor VIIa Inhibitors and Factor Xa Inhibitors;(26) farnesyl-protein transferase inhibitors; (27) fibrates; (28) growthfactor inhibitors, such as modulators of PDGF activity; (29) growthhormone secretagogues; (30) HMG CoA reductase inhibitors, such aspravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a.itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (also known asrosuvastatin, atavastatin, or visastatin); neutral endopeptidase (NEP)inhibitors; (31) hormonal agents, such as glucocorticoids (e.g.,cortisone), estrogens/antiestrogens, androgens/antiandrogens,progestins, and luteinizing hormone-releasing hormone antagonists, andoctreotide acetate; (32) immunosuppressants; (33) mineralocorticoidreceptor antagonists, such as spironolactone and eplerenone; (34)microtubule-disruptor agents, such as ecteinascidins; (35)microtubule-stabilizing agents, such as pacitaxel, docetaxel, andepothilones A-F; (36) MTP Inhibitors; (37) niacin; (38)phosphodiesterase inhibitors, such as PDE III inhibitors (e.g.,cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, andvardenafil); (39) plant-derived products, such as vinca alkaloids,epipodophyllotoxins, and taxanes; (40) platelet activating factor (PAF)antagonists; (41) platinum coordination complexes, such as cisplatin,satraplatin, and carboplatin; (42) potassium channel openers; (43)prenyl-protein transferase inhibitors; (44) protein tyrosine kinaseinhibitors; (45) renin inhibitors; (46) squalene synthetase inhibitors;(47) steroids, such as aldosterone, beclometasone, betamethasone,deoxycorticosterone acetate, fludrocortisone, hydrocortisone (cortisol),prednisolone, prednisone, methylprednisolone, dexamethasone, andtriamcinolone; (48) TNF-alpha inhibitors, such as tenidap; (49) thrombininhibitors, such as hirudin; (50) thrombolytic agents, such asanistreplase, reteplase, tenecteplase, tissue plasminogen activator(tPA), recombinant tPA, streptokinase, urokinase, prourokinase, andanisoylated plasminogen streptokinase activator complex (APSAC); (51)thromboxane receptor antagonists, such as ifetroban; (52) topoisomeraseinhibitors; (53) vasopeptidase inhibitors (dual NEP-ACE inhibitors),such as omapatrilat and gemopatrilat; and (54) other miscellaneousagents, such as, hydroxyurea, procarbazine, mitotane,hexamethylmelamine, and gold compounds.

In certain embodiments, the other therapies that may be used incombination with the compounds provided herein include, but are notlimited to, surgery, endocrine therapy, biologic response modifiers(e.g., interferons, interleukins, and tumor necrosis factor (TNF)),hyperthermia and cryotherapy, and agents to attenuate any adverseeffects (e.g., antiemetics).

In certain embodiments, the other therapeutic agents that may be used incombination with the compounds provided herein include, but are notlimited to, alkylating drugs (mechlorethamine, chlorambucil,cyclophosphamide, melphalan, and ifosfamide), antimetabolites(cytarabine (also known as cytosine arabinoside or Ara-C), HDAC (highdose cytarabine), and methotrexate), purine antagonists and pyrimidineantagonists (6-mercaptopurine, 5-fluorouracil, cytarbine, andgemcitabine), spindle poisons (vinblastine, vincristine, andvinorelbine), podophyllotoxins (etoposide, irinotecan, and topotecan),antibiotics (daunorubicin, doxorubicin, bleomycin, and mitomycin),nitrosoureas (carmustine and lomustine), enzymes (asparaginase), andhormones (tamoxifen, leuprolide, flutamide, and megestrol), imatinib,adriamycin, dexamethasone, and cyclophosphamide. For a morecomprehensive discussion of updated cancer therapies; See,http://www.nci.nih.gov/, a list of the FDA approved oncology drugs athttp://www.fda.gov/cder/cancer/druglistframe.htm, and The Merck Manual,Seventeenth Ed. 1999, the entire contents of which are herebyincorporated by reference.

In another embodiment, the method provided herein comprisesadministration of a compound provided herein, e.g., a compound ofFormula I, or an enantiomer, a mixture of enantiomers, a mixture of twoor more diastereomers, or an isotopic variant thereof, or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof,together with administering one or more chemotherapeutic agents and/ortherapies selected from: alkylation agents (e.g., cisplatin,carboplatin); antimetabolites (e.g., methotrexate and 5-FU); antitumourantibiotics (e.g., adriamymycin and bleomycin); antitumour vegetablealkaloids (e.g., taxol and etoposide); antitumor hormones (e.g.,dexamethasone and tamoxifen); antitumour immunological agents (e.g.,interferon α, β, and γ); radiation therapy; and surgery. In certainembodiments, the one or more chemotherapeutic agents and/or therapiesare administered to the subject before, during, or after theadministration of the compound provided herein.

Such other agents, or drugs, can be administered, by a route and in anamount commonly used therefor, simultaneously or sequentially with thecompound provided herein, e.g., a compound of Formula I, or anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof. When a compoundprovided herein is used contemporaneously with one or more other drugs,a pharmaceutical composition containing such other drugs in addition tothe compound provided herein can be utilized, but is not required.Accordingly, the pharmaceutical compositions provided herein includethose that also contain one or more other active ingredients ortherapeutic agents, in addition to a compound provided herein.

The weight ratio of a compound provided herein to the second activeingredient can be varied, and will depend upon the effective dose ofeach ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound provided herein is combined with aNSAID, the weight ratio of the compound to the NSAID can range fromabout 1,000:1 to about 1:1,000, or about 200:1 to about 1:200.Combinations of a compound provided herein and other active ingredientswill generally also be within the aforementioned range, but in eachcase, an effective dose of each active ingredient should be used.

The compounds provided herein can also be provided as an article ofmanufacture using packaging materials well known to those of skill inthe art. See, e.g., U.S. Pat. Nos. 5,323,907; 5,052,558; and 5,033,252.Examples of pharmaceutical packaging materials include, but are notlimited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials,containers, syringes, and any packaging material suitable for a selectedformulation and intended mode of administration and treatment.

Provided herein also are kits which, when used by the medicalpractitioner, can simplify the administration of appropriate amounts ofactive ingredients to a subject. In certain embodiments, the kitprovided herein includes a container and a dosage form of a compoundprovided herein, e.g., a compound of Formula I, or an enantiomer, amixture of enantiomers, a mixture of two or more diastereomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In certain embodiments, the kit includes a container comprising a dosageform of the compound provided herein, e.g., a compound of Formula I, oran enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; in a containercomprising one or more other therapeutic agent(s) described herein.

Kits provided herein can further include devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, needle-less injectors drip bags, patches,and inhalers. The kits provided herein can also include condoms foradministration of the active ingredients.

Kits provided herein can further include pharmaceutically acceptablevehicles that can be used to administer one or more active ingredients.For example, if an active ingredient is provided in a solid form thatmust be reconstituted for parenteral administration, the kit cancomprise a sealed container of a suitable vehicle in which the activeingredient can be dissolved to form a particulate-free sterile solutionthat is suitable for parenteral administration. Examples ofpharmaceutically acceptable vehicles include, but are not limited to:aqueous vehicles, including, but not limited to, Water for InjectionUSP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection,Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection;water-miscible vehicles, including, but not limited to, ethyl alcohol,polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles,including, but not limited to, corn oil, cottonseed oil, peanut oil,sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

The disclosure will be further understood by the following non-limitingexamples.

EXAMPLES

As used herein, the symbols and conventions used in these processes,schemes and examples, regardless of whether a particular abbreviation isspecifically defined, are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Specifically, butwithout limitation, the following abbreviations may be used in theexamples and throughout the specification: g (grams); mg (milligrams);mL (milliliters); μL (microliters); L, (liter); mM (millimolar); μM(micromolar); Hz (Hertz); MHz (megahertz); mmol (millimoles); e.g.(equivalent); hr or hrs (hours); min (minutes); MS (mass spectrometry);NMR (nuclear magnetic resonance); ESI (electrospray ionization); HPLC(high-performance liquid chromatography or high pressure liquidchromatography); ACN, (acetonitrile); CDCl₃ (deuterated chloroform); DCM(dichloromethane); DMF (N,N-dimethylformamide); DMSO(dimethylsulfoxide); DMSO-d₆ (deuterated dimethylsulfoxide); EtOAc(ethyl acetate); Et₂O (diethyl ether); EtOH (ethanol); MeOH (methanol);PE (petroleum ether); THF (tetrahydrofuran); DIPEA(N,N-diisopropylethylamine); TEA (triethylamine); TFA (trifluoroaceticacid); BOP (benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate); HATU(2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate); TBTU(O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate);DIPC (1,3-diisopropylcarbodiimide); Me (methyl); Et (ethyl); iPr,(isopropyl); tBu (tert-butyl); Boc (tert-butoxylcarbony); Bn (benzyl);Ph (phenyl); and AcO (acetate).

HPLC-MS analyses were performed on Waters HPLC 2790 coupled with Watersmicromass ZQ 4000 (Model MAA050) as a mass detector and with Waters 2487UV as a UV-visible detector, using a KINETEX™ reversed phase column (5μM XB-C18-100 Å, 50×4.6 mm; Phenomenex, 00B-4605-E0). The mobile phasewere eluent A (water, 0.05% TFA) and eluent B (CH₃OH, 0.05% TFA). TheHPLC was run at 1 mL/min with a linear gradient from 10% B to 90% B for8 min, followed by 90% B isocratic for 2 min, with the total run time of10 min.

For all of the following examples, standard work-up and purificationmethods known to those skilled in the art can be utilized. Unlessotherwise indicated, all temperatures are expressed in ° C. (degreesCentigrade). All reactions conducted at room temperature unlessotherwise noted. Synthetic methodologies herein are intended toexemplify the applicable chemistry through the use of specific examplesand are not indicative of the scope of the disclosure.

Example 1A Cell Proliferation Assay

The biological activity of a test compound was determined using cellproliferation assays. The activity against wild-type ERBB1 wasdetermined using A431 human epidermoid carcinoma cells (ATCC) and humanepidermal keratinocytes, neonatal, or HEKn cells (ATCC). The activityagainst mutant ERBB1 was determined using HCC827 human NSCLCadenocarcinoma cells (ATCC), which has a deletion of E746-A759 in exon19. The activity against a drug-resistant mutant ERBB1 was determinedusing H1975 human NSCLC adenocarcinoma cells (ATCC), which has the T790Mmutation in-cis with the L858R mutation.

A431 cells were grown in DMEM (Invitrogen) supplemented with 10% FBS(Lonza), 1% penicillin-streptomycin, and 2 mM glutamine (Invitrogen).HEKn cells were grown in EPILIFE® (Invitrogen) supplemented with HKGS(Invitrogen). HCC827 and H1975 were cultured in RPMI1640 supplementedwith 10% FBS (Lonza), 1% penicillin-streptomycin, and 2 mM glutamine(Invitrogen). Cells were maintained and propagated at 37° C. and 5% CO₂in a humidified cell culture incubator. Aliquots of cells from earlypassages were preserved for liquid nitrogen storage. Frozen vials ofcells were thawed at 37° C. water bath. Cells were spun to removefreezing medium. The newly revived frozen cells were adapted in culturefor 10 days before used for compound testing. Cells used in the assaywere less than 20 subculture passages or 3 months in culture.

The test compounds were dissolved in dimethylsulfoxide (DMSO) and storedat −20° C. before testing. For the cell proliferation assays, cells wereseeded in 96-well plates (Costar, 3917) at various numbers: A431 cellsat 2,000 cells per well, HEKn, HCC827, and H1975 at 1,000 cells perwell. The cells were placed in a culture incubator overnight. Next day,test compounds in DMSO were added to the cells and placed back in theculture incubator for 72 hrs. In the meantime, the cell numbers at timezero of the compound treatment (T0) was measured by EnerCount (CodexBioSolutions). At the end of the compound treatment, the cell numberswere again measured by EnerCount as T72 values. The untreated controls(Ctrl) were cell numbers recorded from the 0.1% DMSO treatment. Thepercent growth inhibition by the test compound was calculated by theformula: (1-(T72−T0)/(Ctrl−T0))×100. The GI₅₀, the compoundconcentration at which 50% of cell growth is inhibited, was determinedfrom the 10-point dose-response growth inhibition using non-linearsigmoidal curve fitting using GraphPad Prism.

The results are summarized in Tables 1 and 2, wherein A represents avalue no greater than 500 nM, B represents a value greater than 500 nMbut no greater than 1 μM, C represents a value greater than 1 μM but nogreater than 5 μM, and D represents a value greater than 5 μM; andwherein A′ represents a ratio of greater than 10, B′ represents a ratioof no greater than 10 but no less than 5, C′ represents a ratio of nogreater than 5 but no less than 2, and D′ represents a ratio of nogreater than 2.

TABLE 1 Inhibition of Cell Proliferation GI₅₀ Cmpd. HCC827 H1975 HEKnA431 B1 A A D C C1 A A C C C2 A A C C Erlotinib 7.0 4381 2200 Afatinib1.0 120 21 1.4 CO-1686 32 109 2500

TABLE 2 Selectivity Ratio (Wild-type ERBB1/Mutant ERBB1) HEKn/ Cmpd.HCC827 A431/HCC827 HEKn/H1975 A431/H1975 Erlotinib A′ D′ Afatinib A′ D′D′ D′ CO-1686 A′ A′

Example 1 Synthesis of (R)-tert-butyl3-(2-amino-7,8-dihydro-1H-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]imidazol-1-yl)azepane-1-carboxylate5

The synthesis of (R)-tert-butyl3-(2-amino-7,8-dihydro-1H-[1,4]dioxino[2′,3′:3,4]benzo[1,2-c]imidazol-1-yl)azepane-1-carboxylate5 is shown in Scheme 1.

5-Fluoro-2,3-dihydrobenzo[b][1,4]dioxine 1. To a mixture of3-fluorobenzene-1,2-diol (25.0 g, 195 mmol) and K₂CO₃ (81.0 g, 585 mmol)in DMF (150 mL) was added 1,2-dibromoethane (33.6 ml, 390 mmol). Afterstirred at 110° C. temperature overnight, the reaction mixture waspoured into water (500 mL), extracted with EtOAc (3×500 mL). Thecombined extracts were washed with water, brine, dried over anhydrousNa₂SO₄, and concentrated under reduced pressure, and purified by silicagel column chromatography with PE/EtOAc (40:1) to give compound 1.

5-Fluoro-6-nitro-2,3-dihydrobenzo[b][1,4]dioxine 2. To a solution of 85%HNO₃ (100 mL) at 0° C. was added5-fluoro-2,3-dihydrobenzo[b][1,4]dioxine 1 (20.0 g, 130 mmol) inportions. After stirred at 0° C. for 30 min, the reaction mixture waspoured over ice water (800 mL), extracted with EtOAc (3×500 mL). Thecombined organic extracts were washed with brine, dried over anhydrousNa₂SO₄, and evaporated under reduced pressure, and purified by silicagel column chromatography with PE/DCM (4:1) to give compound 2 in 18.9%yield (4.88 g).

(R)-Tert-butyl3-((6-nitro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)azepane-1-carboxylate3. To a solution of 5-fluoro-6-nitro-2,3-dihydrobenzo[b][1,4]dioxine 2(1.2 g, 6.03 mmol) in dry N-methyl-2-pyrrolidone (NMP) (15 mL) wereadded (R)-tert-butyl 3-aminoazepane-1-carboxylate (1.35 g, 6.33 mmol)and DIPEA (1.5 mL). After stirred at 120° C. overnight, the reactionmixture was cooled to room temperature and water (200 mL) was added. Thereaction mixture was extracted with EtOAc (200 mL×3). The combinedorganic extracts were washed with brine, dried over anhydrous Na₂SO₄,evaporated under reduced pressure, and purified on a silica gel columnwith PE/EtOAc (5:1) to give compound 3 in 97% yield (2.3 g).

(R)-Tert-butyl3-((6-amino-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)amino)azepane-1-carboxylate4. To a solution of (R)-tert-butyl3-(6-nitro-2,3-dihydrobenzo[b][1,4]dioxin-5-ylamino)azepane-1-carboxylate3 (2.3 g, 5.85 mmol) in MeOH (100 mL) under nitrogen atmosphere wasadded 10% Pd/c (400 mg). The reaction mixture was stirred at roomtemperature under hydrogen atmosphere overnight. The catalyst wasfiltrated off through a pad of celite and the filtrate was concentratedin vacuo to provide compound 4 in 94.3% yield ((2.0 g), which was useddirectly in the next step without further purification.

(R)-Tert-butyl3-(2-amino-7,8-dihydro-1H-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]imidazol-1-yl)azepane-1-carboxylate5. To a solution of (R)-tert-butyl3-(6-amino-2,3-dihydrobenzo[b][1,4]dioxin-5-ylamino)azepane-1-carboxylate4 (2.1 g, 5.78 mmol) in 50 mL of MeOH/ACN/H₂O (3:1:1) was added BrCN(1.05 g). After stirred at 50° C. overnight, the reaction mixture wasconcentrated in vacuo and the residue was purified on a silica gelcolumn with DCM/MeOH (45:1) to furnish compound 5 in 93.5% yield (2.1g). MS observed (M+H⁺) for C₂₀H₂₈N₄O₄: 389.30; HPLC retention time: 3.59min.

Example 2 Synthesis of(R)—N-(1-(1-acryloylazepan-3-yl)-7,8-dihydro-1H-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]imidazol-2-yl)-2-methylisonicotinamideC1

The synthesis of(R)—N-(1-(1-acryloylazepan-3-yl)-7,8-dihydro-1H-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]imidazol-2-yl)-2-methylisonicotinamideC1 is shown in Scheme 2.

(R)-Tert-butyl3-(2-(2-methylisonicotinamido)-7,8-dihydro-1H-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]imidazol-1-yl)azepane-1-carboxylate6. 2-Methylisonicotinic acid (0.050 g, 0.036 mmol) and HATU (0.150 g,0.040 mmol) were dissolved in a DMF mixture (4 mL), followed by additionof 10 molar percent of 4-simethylaminopyridine (DMAP) and DIPEA (0.18mL, 1 mmol). The reaction mixture was stirred for 10 min before addingto a solution of (R)-tert-butyl3-(2-amino-7,8-dihydro-1H-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]imidazol-1-yl)azepane-1-carboxylate5 (0.130 g, 0.033 mmol) in DMF (1 mL). After one hour of stirring, thereaction was stripped off solvents. The residue was dissolved in EtOAc(200 mL). The organic solution was washed with saturated NaHCO₃ (10 mL),brine (40 mL), dried with anhydrous Na₂SO₄, and concentrated undervacuum. The residue obtained was purified on a silica gel column (0-2%methanol in DCM) to afford (R)-Tert-butyl3-(2-(2-methylisonicotinamido)-7,8-dihydro-1H-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]imidazol-1-yl)azepane-1-carboxylate6 in 83% yield (0.139 g).

(R)—N-(1-(Azepan-3-yl)-7,8-dihydro-1H-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]imidazol-2-yl)-2-methylisonicotinamide7. (R)-Tert-butyl3-(2-(2-methylisonicotinamido)-7,8-dihydro-1H-[1,4]dioxino[2′,3′:3,4]benzo[1,2-c]imidazol-1-yl)azepane-1-carboxylate6 (139 mg, 0.027 mmol) was dissolved in DCM (2 mL). Trifluoroacetic acid(1.0 mL) was added and the reaction mixture was stirred at roomtemperature for 1 hr. The solvents were stripped off. The residueobtained was dissolved in 50 mL of DCM and washed with saturated NaHCO₃(15 mL), brine (20 mL), dried with anhydrous Na₂SO₄, and concentrated toyield(R)—N-(1-(azepan-3-yl)-7,8-dihydro-1H-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]imidazol-2-yl)-2-methylisonicotinamide7 in 91% yield (100 mg).

(R)—N-(1-(1-acryloylazepan-3-yl)-7,8-dihydro-1H-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]imidazol-2-yl)-2-methylisonicotinamideC1. Acrylic acid (0.25 mmol, 24 mg) and HATU (94 mg, 0.25 mmol) weremixed in DMF (8 mL), followed by addition of DMAP (0.022 mmol, 4 mg) andDIPEA (0.6 mmol, 0.1 mL). After 5 minutes of stirring, the mixture wasadded to a solution of(R)—N-(1-(azepan-3-yl)-7,8-dihydro-1H-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]imidazol-2-yl)-2-methylisonicotinamide7 (91 mg, 0.22 mmol) in DMF (1 mL). The reaction mixture was furtherstirred overnight and then was diluted with DCM (60 mL), washed withsaturated sodium bicarbonate solution (10 mL) and water (10 mL), driedwith anhydrous sodium sulfate, and concentrated. The residue obtainedwas purified on a silica gel column with 1-10% MeOH in DCM to yield(R)—N-(1-(1-acryloylazepan-3-yl)-7,8-dihydro-1H-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]imidazol-2-yl)-2-methylisonicotinamideC1 in 27% yield (25 mg). MS calculated for C₂₅H₂₇N₅O₄: 460.7 (M−H⁻);HPLC retention time: 2.34 min.

Example 3 Synthesis of(R)—N-(1-(1-acryloylazepan-3-yl)-7,8-dihydro-1H-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]imidazol-2-yl)-2-(trifluoromethyl)isonicotinamideB1

(R)—N-(1-(1-Acryloylazepan-3-yl)-7,8-dihydro-1H-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]imidazol-2-yl)-2-(trifluoromethyl)isonicotinamideB1 was synthesized according to the procedures as described in Example2. MS calculated for C₂₅H₂₄F₃N₅O₄: 514.8 (M−H⁻); HPLC retention time:2.55 min.

Example 4 Synthesis of(R)—N-(1-(1-acryloylazepan-3-yl)-7,8-dihydro-1H-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]imidazol-2-yl)-2-methoxyisonicotinamideC2

(R)—N-(1-(1-Acryloylazepan-3-yl)-7,8-dihydro-1H-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]imidazol-2-yl)-2-methoxyisonicotinamideC2 was synthesized according to the procedures as described in Example2. MS calculated for C₂₅H₂₇N₅O₅: 476.6 (M−H⁻); HPLC retention time: 2.78min.

Example 5 Synthesis of(R,E)-N-(1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-7,8-dihydro-1H-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]imidazol-2-yl)-2-(trifluoromethyl)isonicotinamideC3

(R,E)-N-(1-(1-(4-(Dimethylamino)but-2-enoyl)azepan-3-yl)-7,8-dihydro-1H-[1,4]dioxino[2′,3′:3,4]benzo[1,2-d]imidazol-2-yl)-2-(trifluoromethyl)isonicotinamideC3 was synthesized according to the procedures as described in Example2. MS calculated for C₂₈H₃₁F₃N₆O₄: 571.5 (M−H⁻); HPLC retention time:2.10 min.

The examples set forth above are provided to give those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the claimed embodiments, and are not intended to limit thescope of what is disclosed herein. Modifications that are obvious topersons of skill in the art are intended to be within the scope of thefollowing claims. All publications, patents, and patent applicationscited in this specification are incorporated herein by reference as ifeach such publication, patent or patent application were specificallyand individually indicated to be incorporated herein by reference.

What is claimed is:
 1. A method for treating or ameliorating one or moresymptoms of a proliferative disease in a subject, comprisingadministering to the subject a therapeutically effective amount of acompound of Formula I:

or a single enantiomer, a racemic mixture, a mixture of diastereomers,or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof; wherein the proliferative disease is lungcancer, kidney cancer, or squamous cell carcinoma; and wherein: R¹ is—C(O)CH═CHR^(1f), wherein R^(1f) is hydrogen, dimethylaminomethyl,pyrrolidin-1-ylmethyl, or piperidin-1-ylmethyl; or R¹ is:

R² is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; L¹ is a bond, —O—,—S—, —N(R^(1A))—, or —C(R^(1A)R^(1B))—, wherein each R^(1A) and R^(1B)is independently hydrogen, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl;L² is C₃₋₁₀ cycloalkylene, C₆₋₁₄ arylene, C₇₋₁₅ aralkylene,heteroarylene, or heterocyclylene; T is a bond, —O—, —S—, —N↑, —N(R⁴)—,or —C(R⁴)═; U is a bond, —O—, —S—, —N↑, —N(R⁵)—, or —C(R⁵)═; V is abond, —O—, —S—, —N↑, —N(R⁶)—, or —C(R⁶)═; W is a bond, —O—, —S—, —N↑,—N(R⁷)—, or —C(R⁷)═; X and Y are each independently C or N; Z is NR^(2A)or CR^(2A)R^(2B), wherein each R^(2A) and R^(2B) is independentlyhydrogen, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; R⁴, R⁵, R⁶, andR⁷ are each independently (a) hydrogen, cyano, halo, or nitro; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); with proviso that at leasttwo of R⁴, R⁵, R⁶, and R⁷ are not hydrogen; and with the proviso that R⁴and R⁵, R⁵ and R⁶, or R⁶ and R⁷ are linked together to form heteroarylor heterocyclyl; and each R^(1a), R^(1b), R^(1c), and R^(1d) isindependently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; orR^(1a) and R^(1c) together with the C and N atoms to which they areattached form heterocyclyl; or R^(1b) and R^(1c) together with the Natom to which they are attached form heterocyclyl; with the proviso thatno more than one of T, U, V, and W is a bond; wherein each alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl,aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclyleneis optionally substituted with one or more substituents Q, where each Qis independently selected from (a) oxo, cyano, halo, and nitro; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, and heterocyclyl, each of which is furtheroptionally substituted with one or more substituents Q^(a); and (c)—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c),—OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c),—OC(═NR^(a))NR^(b)R^(c), —OP(O)(OR^(a))₂, —OS(O)R^(a), —OS(O)₂R^(a),—OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d),—NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c),—NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),—NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b),R^(c), and R^(d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl, each of which is optionally substitutedwith one or more substituents Q^(a); or (iii) R^(b) and R^(c) togetherwith the N atom to which they are attached form heterocyclyl, optionallysubstituted with one or more substituents Q^(a); wherein each Q^(a) isindependently selected from the group consisting of (a) oxo, cyano,halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl; and(c) —C(O)R^(f), —C(O)OR^(f), —C(O)NR^(g)R^(h), —C(NR^(f))NR^(g)R^(h),—OR, —OC(O)R^(f), —OC(O)OR^(f), —OC(O)NR^(g)R^(h),—OC(═NR^(f))NR^(g)R^(h), —OP(O)(OR^(f))₂, —OS(O)R^(f), —OS(O)₂R^(f),—OS(O)NR^(g)R^(h), —OS(O)₂NR^(g)R^(h), —NR^(g)R^(h), —NR^(f)C(O)R^(k),—NR^(f)C(O)OR^(k), —NR^(f)C(O)NR^(g)R^(h), —NR^(f)C(═NR^(k))NR^(g)R^(h),—NR^(f)S(O)R^(k), —NR^(f)S(O)₂R^(k), —NR^(f)S(O)NR^(g)R^(h),—NR^(f)S(O)₂NR^(g)R^(h), —SR^(f), —S(O)R^(f), —S(O)₂R^(f),—S(O)NR^(g)R^(h), and —S(O)₂NR^(g)R^(h); wherein each R^(f), R^(g),R^(h), and R^(k) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(g) and R^(h) together with theN atom to which they are attached form heterocyclyl.
 2. The method ofclaim 1, wherein the compound has the structure of Formula IV:

or a single enantiomer, a racemic mixture, a mixture of diastereomers,or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof, wherein: m is an integer of 0, 1, 2, 3, 4,5, 6, 7, 8, 9, or 10; n is an integer of 0, 1, 2, 3, 4, 5, or 6; eachR^(L) is independently (i) hydrogen; or (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀o cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl,or heterocyclyl, each of which is optionally substituted with one ormore substituents Q; or (iii) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); or two R^(L) together, whenthere are two or more R^(L) attached to the same ring, are linkedtogether to form (i) a bond, —O—, —NR^(N)—, or —S—; or (ii) C₁₋₆alkylene, C₁₋₆ heteroalkylene, C₂₋₆ alkenylene, or C₂₋₆heteroalkenylene, each of which is optionally substituted with one ormore substituents Q; and R^(N) is (a) hydrogen; (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl, each of which is optionally substitutedwith one or more substituents Q; (c) —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d)—NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c).
 3. The method of claim 1,wherein the compound has the structure of Formula V:

or a single enantiomer, a racemic mixture, a mixture of diastereomers,or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof.
 4. The method of claim 3, wherein R² isC₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which is optionallysubstituted with one or more substituents Q.
 5. The method of claim 4,wherein R² is phenyl, pyridinyl, pyridazinyl,benzo[c][1,2,5]oxodiazolyl, or benzo[c][1,2,5]thiodiazolyl, each ofwhich is optionally substituted with one or more substituents Q.
 6. Themethod of claim 3, wherein R⁵ and R⁶ are linked together to formheterocyclyl, optionally substituted with one or more substituents Q. 7.The method of claim 6, wherein R⁵ and R⁶ are linked together to formheterocyclyl selected from:


8. The method of claim 3, wherein R⁶ and R⁷ are linked together to formheterocyclyl, optionally substituted with one or more substituents Q. 9.The method of claim 8 wherein R⁶ and R⁷ are linked together to formheterocyclyl selected from:

wherein p is an integer of 1, 2, 3, 4, 5, or
 6. 10. The method of claim1, wherein the compound is selected from:

and single enantiomers, racemic mixtures, mixtures of diastereomers, andisotopic variants thereof; and pharmaceutically acceptable salts andsolvates thereof.
 11. The method of claim 1, wherein the compound isselected from:

and single enantiomers, racemic mixtures, mixtures of diastereomers, andisotopic variants thereof; and pharmaceutically acceptable salts andsolvates thereof.
 12. The method of claim 1, wherein the compound isselected from:

and isotopic variants thereof; and pharmaceutically acceptable salts andsolvates thereof.
 13. The method of claim 1, wherein the compound isselected from:

and isotopic variants thereof; and pharmaceutically acceptable salts andsolvates thereof.
 14. The method of claim 1, wherein the cancer isdrug-resistant.
 15. The method of claim 1, wherein the cancer containsan ERBB variant.
 16. The method of claim 15, wherein the ERBB variant isan EGFR variant.
 17. The method of claim 16, wherein the EGFR variantcontains one or more deletions, insertions, or substitutions at theamino acid positions of 689, 700, 709, 715, 719, 720, 746-759, 761-765,767-775, 783, 784, 790, 796, 826, 839, 846, 858, 861, and
 863. 18. Themethod of claim 16, wherein the EGFR variant contains one or moredeletions, insertions, or substitutions at the amino acid positions of719, 746-751, 790, and
 858. 19. The method of claim 16, wherein the EGFRvariant contains one, two, or more deletions, insertions, and/orsubstitutions, each independently selected from G719C, G719S, G719A,ΔE746-A750, ΔE746-T751, ΔE746-A750 (ins RP), ΔD761-E762 (ins EAFQ),ΔS768-D770 (dup SVD), ΔV769-D770 (ins ASV), ΔD770-N771 (ins SVQ),ΔP772-H773 (ins PR), ΔH773-V774 (ins NPH), ΔH773-V774 (ins H),ΔH773-V774 (ins PH), and ΔH773-V774 (ins GNPH), T790M, and L858R. 20.The method of claim 16, wherein the EGFR variant contains T790M, L858R,or a combination thereof.
 21. The method of claim 15, wherein the ERBBvariant is a HER2 variant.
 22. The method of claim 21, wherein the HER2is overexpressed in the cancer.
 23. The method of claim 14, wherein thecancer is resistant to an EGFR inhibitor.
 24. The method of claim 23,wherein the cancer is resistant to afatinib, canertinib, dacomitinib,erlotinib, gefitinib, icotinib, lapatinib, neratinib, pelitinib,varlitinib, or a combination thereof.
 25. The method of claim 1, whereinthe cancer is lung cancer.
 26. The method of claim 1, wherein the canceris non-small cell lung cancer.
 27. The method of claim 1, wherein thecancer is relapsed or refractory.
 28. The method of claim 1, wherein thesubject is a human.
 29. The method of claim 1, wherein the cancer iskidney cancer.
 30. The method of claim 1, wherein the cancer is squamouscell carcinoma.